Histone demethylase inhibitors

ABSTRACT

The present disclosure relates generally to compositions and methods for treating cancer and neoplastic disease. Provided herein are substituted pyridine derivative compounds, and compositions (including pharmaceutical compositions) that include these compounds. The subject compounds and compositions are useful for inhibition of at least one histone demethylase. Furthermore, the subject compounds and compositions are useful for the treatment of cancer or neoplastic disease, such as prostate cancer, breast cancer, bladder cancer, lung cancer, melanoma, retinoblastoma, or multiple endocrine neoplasia type 1.

RELATED APPLICATIONS

This Application is a continuation of U.S. application Ser. No.15/391,773, filed Dec. 27, 2016, which claims priority benefit of U.S.Provisional Application Ser. No. 62/271,654, filed Dec. 28, 2015, andSer. No. 62/438,435, filed Dec. 22, 2016, the contents of which areincorporated herein by reference in their entireties for all purposes.

FIELD OF INVENTION

This disclosure is related to histone demethylase inhibitors.

BACKGROUND

A need exists in the art for an effective treatment of cancer andneoplastic disease.

SUMMARY

The present embodiments provide substituted pyridine derivativecompounds useful for inhibition of at least one histone demethylase, andpharmaceutical compositions comprising these compounds. Additionally,the subject compounds and compositions are useful for the treatment ofcancer, such as prostate cancer, breast cancer, bladder cancer, lungcancer, melanoma, and the like. The substituted pyridine derivativecompounds described herein are based upon a disubstituted pyridine ringbearing at the 4-position a carboxylic acid, a carboxylic acid ester, ora carboxylic acid bioisostere thereof, and bearing at the 3-position asubstituted amino group.

At least one embodiment provides a compound having the structure ofFormula 1:

-   -   wherein a compound of Formula 1 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:        -   n is 0, 1, or 2;        -   R⁴ is hydrogen or optionally substituted C₁-C₆ alkyl;        -   R⁶ is hydrogen or X—Y, wherein            -   X is a bond, O, S, N(R), C(O), N(R)C(O), C(O)N(R), or                optionally substituted C₁-C₃ alkyl, in which R is                hydrogen or optionally substituted alkyl, and            -   Y is optionally substituted alkyl, cycloalkyl,                heterocyclyl, aryl, or heteroaryl;        -   R⁵, R⁷, and R⁸ are each independently selected from            hydrogen, halogen, hydroxyl, cyanyl, N(R¹)(R²), or            optionally substituted C₁-C₆ alkyl, C₁-C₆ alkynyl, C₁-C₆            alkenyl, C₁-C₆ alkoxy, C₃-C₇ carbocyclyl, C₃-C₇            carbocyclyloxy, C₄-C₁₂ carbocyclylalkyl, C₄-C₁₂            carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₆-C₁₀            aryl-S, C₆-C₁₀ to aryl-SO₂, C₇-C₁₄ aralkoxy, heteroaryl,            heteroaryloxy, heterocyclyl, heterocyclyloxy,            heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S,            wherein        -   R¹ is hydrogen or optionally substituted alkyl, and        -   R² is optionally substituted alkyl, aryl, heteroaryl,            heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl-CO,            heteroaryl-CO, cycloalkyl-CO, or alkyl-CO.

In at least one embodiment of a compound of Formula 1, n is 0. In atleast one embodiment of a compound of Formula 1, n is 1. In at least oneembodiment of a compound of Formula 1, R⁴ is methyl. In one embodimentof the compound of Formula 1, each of R⁵, R⁷, and R⁸ are hydrogen.

At least one embodiment provides a composition comprising a compound ofFormula 1. In at least one embodiment, the composition is apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a compound of Formula 1.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 1 or a composition comprising a compound ofFormula 1.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 1. Anotherembodiment provides use of a compound of Formula 1 in a medicament fortreating cancer. A related embodiment provides use of a compound,composition, or pharmaceutical composition comprising the compound ofFormula 1 in manufacture of a medicament for treating cancer orneoplastic disease, wherein the medicament is administered to a patientin need thereof. The cancer or neoplastic disease being treated, or forwhich the medicament is manufactured, may be prostate cancer, breastcancer, bladder cancer, lung cancer, melanoma, retinoblastoma, ormultiple endocrine neoplasia type 1.

At least one embodiment provides a compound of Formula 2:

-   -   wherein a compound of Formula 2 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:        -   n is 0, 1, or 2;        -   R⁴ is hydrogen or optionally substituted C₁-C₆ alkyl; and        -   R³ is N(R)(R⁹), N(R)C(O), C(O)N(R), or optionally            substituted C₃-C₇ carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂            carbocyclylalkyl, C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl,            C₆-C₁₀ aryloxy, C₆-C₁₀ aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄            aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl,            heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy or            heteroaryl-S, wherein            -   R is hydrogen or optionally substituted alkyl, and            -   R⁹ is optionally substituted C₃-C₇ carbocyclyl, C₃-C₇                carbocyclyloxy, C₄-C₁₂ carbocyclylalkyl, C₄-C₁₂                carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₆-C₁₀                aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄ aralkoxy, heteroaryl,                heteroaryloxy, heterocyclyl, heterocyclyloxy,                heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S.

In at least one embodiment of a compound of Formula 2, n is 0. In atleast one embodiment of a compound of Formula 2, n is 1.

In at least one embodiment of a compound of Formula 2, R⁴ is methyl. Inat least one embodiment of a compound of Formula 2, R⁴ is hydrogen.

In at least one embodiment of a compound of Formula 2, R³ is N(R)(R⁹).In some embodiments of a compound of Formula 2 in which R³ is N(R)(R⁹),R is methyl.

In some embodiments of a compound of Formula 2 in which R³ is N(R)(R⁹),R⁹ is methylphenyl (“tolyl”) or isopropylphenyl. In other embodiments ofa compound of Formula 2, R³ is N(R)(R⁹) wherein R⁹ istrifluoroethoxyphenyl. In particular embodiments of a compound ofFormula 2, R³ is N(R)(R⁹), R is methyl, and R⁹ is optionally substitutedhalophenyl, alkylphenyl, haloalkylphenyl, halo(alkyloxy)phenyl orhaloalkyloxyphenyl. In particular embodiments of a compound of Formula2, R³ is N(R)(R⁹), R is methyl, and R⁹ is optionally substitutedmethylphenyl. In particular embodiments of Formula 2, R³ is N(R)(R⁹), Ris methyl, and R⁹ isopropylphenyl.

In some embodiments of a compound of Formula 2, R³ is optionallysubstituted C₆-C₁₀ aryl. In some embodiments of a compound of Formula 2,R³ is, for example, optionally substituted methylphenyl (“tolyl”) (suchas 2-toyl (o-toyl), or 4-tolyl (p-tolyl)), dimethylphenyl (such as2,6-dimethyl propylphenyl), ethylphenyl (such as 2- or 4-ethylphenyl),propylphenyl, isopropylphenyl (such as 2- or 4-isopropylphenyl),n-propylphenyl, butylphenyl, pentylphenyl, propyl-methylphenyl,cyclopropylphenyl, cyclopropyl-methylphenyl, cyclobutylphenyl.

In some embodiments of a compound of Formula 2, R³ is optionallysubstituted halo-C₆-C₁₀ aryl, such as optionally substitutedfluorophenyl, diflurophenyl, or fluro-chlorophenyl. In some embodiments,the optionally substituted halo-C₆-C₁₀ aryl is a halo-alkyloxyphenyl,such as fluoro-methoxyphenyl.

In some embodiments, of a compound of Formula 2, R³ is an optionallysubstituted alkyloxy-alkynyl; such as, for example,ethyloxy-methylphenyl, isopropoxy-methylphenyl,cyclopropylmethyloxy-methylphenyl. In some embodiments of a compound ofFormula 2, R³ is haloalkyloxy-alkylphenyl, such as ahaloalkyloxy-methylphenyl; for example trifluoroethoxy-methylphenyl. Insome embodiments of a compound of Formula 2, R³ ishaloalkyloxy-halophenyl, such as a haloalkyloxy-fluorophenyl; forexample trifluoroethoxy-fluorophenyl. In some embodiments of a compoundof Formula 2, R³ is substituted cycloalkyloxyphenyl. In some embodimentsof a compound of Formula 2, R³ is substituted C₄-C₁₂ carbocyclylalkoxy,such as cycloalkyloxymethylphenyl, in particular(cyclopropylmethoxy)methylphenyl.

In some embodiments, R³ is optionally substituted heterocyclyl, such asthoile (thiophen), pyrrolidinyl, benzylfuranyl, indolinyl, quinolin, orpyranyl. In some embodiments, R³ is optionally substitutedquinolinphenyl.

In particular embodiments of a compound of Formula 2, R³ is selectedfrom chlorophenyl, difluorophenyl, chlorofluorophenyl,(trifluoroethyl)phenyl, (trifluoropropyl)phenyl, methylphenyl (“tolyl”),dimethylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl,hexylphenyl, (cyclopropylethyl)phenyl, cyclopropylphenyl,cyclobutylphenyl, cyclopentylphenyl, cyclohexylphenyl,(cyclobutylmethyl)phenyl, propoxyphenyl, (propyl-methoxy)phenyl,(trifluoroethoxy)phenyl, (trifluoroethoxy)fluorophenyl,(trifluoroethoxy)dimethylphenyl, (propoxy)methylphenyl,(difluoromethoxy)methylphenyl, (quinolinyl)methylphenyl,(dihydroquinolinyl)methylphenyl, indolinylphenyl, dimethylaminophenyl,pyranylphenyl, methyldihydrobenzofuranyl, (indolinyl)methylphenyl, or(pyrrolidinyl)methyl-phenyl, or thiole.

In particular embodiments of a compound of Formula 2, R⁹ is selectedfrom chlorophenyl, difluorophenyl, chlorofluorophenyl,(trifluoroethyl)phenyl, (trifluoropropyl)phenyl, methylphenyl (tolyl),dimethylphenyl, ethylphenyl, propylphenyl, butylphenyl, pentylphenyl,hexylphenyl, (cyclopropylethyl)phenyl, cyclopropylphenyl,cyclobutylphenyl, cyclopentylphenyl, cyclohexylphenyl,(cyclobutylmethyl)phenyl, propoxyphenyl, (propylmethoxy)phenyl,(trifluoroethoxy)phenyl, (trifluoroethoxy)fluorophenyl,(trifluoroethoxy)dimethylphenyl, (propoxy)methylphenyl,(difluoromethoxy)methylphenyl, (quinolinyl)methylphenyl,(dihydroquinolinyl)methylphenyl, indolinylphenyl, dimethylaminophenyl,pyranyl-phenyl, methyldihydrobenzofuranyl, (indolinyl)methylphenyl, or(pyrrolidinyl)methylphenyl, or thiole.

At least one embodiment provides a composition comprising a compound ofFormula 2. In at least one embodiment, the composition is apharmaceutical composition, which comprises at least onepharmaceutically acceptable excipient and a compound of Formula 2.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 2 or a composition comprising a compound ofFormula 2.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 2. Anotherembodiment provides for use of a compound of Formula 2 in a medicamentfor treating cancer or neoplastic disease. A related embodiment providesuse of a compound, composition, or pharmaceutical composition comprisingthe compound of Formula 2 in manufacture of a medicament for treatingcancer or neoplastic disease, wherein the medicament is administered toa patient in need thereof. The cancer or neoplastic disease beingtreated, or for which the medicament is manufactured, may be prostatecancer, breast cancer, bladder cancer, lung cancer, melanoma,retinoblastoma, or multiple endocrine neoplasia type 1.

At least one embodiment provides a compound having the structure ofFormula 3:

-   -   wherein a compound of Formula 3 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:    -   n is 0, 1, or 2;    -   R⁶ is X—Y, wherein        -   X is a bond, O, S, N(R), C(O), N(R)C(O), C(O)N(R), or            optionally substituted C₁-C₃ alkyl,        -   in which R is hydrogen or optionally substituted alkyl, and        -   Y is optionally substituted alkyl, cycloalkyl, heterocyclyl,            aryl, or heteroaryl; and    -   R⁵, R⁷, and R⁸ are each independently selected from hydrogen,        halogen, hydroxyl, cyanyl, or N(R¹)(R²), or optionally        substituted C₁-C₆ alkyl, C₁-C₆ alkynyl, C₁-C₆ alkenyl, C₁-C₆        alkoxy, C₃-C₇ carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂        carbocyclylalkyl, C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀        aryloxy, C₆-C₁₀ aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄ aralkoxy,        heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy,        heterocyclylalkyl, heterocyclylalkoxy, or heteroaryl-S, in which        -   R¹ is hydrogen or optionally substituted alkyl, and        -   R² is optionally substituted alkyl, aryl, heteroaryl,            heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl-CO,            heteroaryl-CO, cycloalkyl-CO, or alkyl-CO.

In one embodiment of a compound of Formula 3, n is 0. In one embodimentof a compound of Formula 3, n is 1. In one embodiment of the compound ofFormula 3, each of R⁵, R⁷, and R⁸ are hydrogen.

At least one embodiment provides a composition comprising a compound ofFormula 3. In at least one embodiment, a composition comprising acompound of Formula 3 is a pharmaceutical composition, which includes atleast one pharmaceutically acceptable excipient.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 3 or a composition comprising Formula 3 thatmay be a pharmaceutical composition.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 3. Anotherembodiment provides for use of a compound of Formula 3 in a medicamentfor treating cancer or neoplastic disease. A related embodiment providesuse of a compound, composition, or pharmaceutical composition comprisingthe compound of Formula 3 in manufacture of a medicament for treatingcancer or neoplastic disease, wherein the medicament is administered toa patient in need thereof. The cancer or neoplastic disease beingtreated, or for which the medicament is manufactured, may be prostatecancer, breast cancer, bladder cancer, lung cancer, melanoma,retinoblastoma, or multiple endocrine neoplasia type 1.

At least one embodiment provides a compound of Formula 4:

-   -   wherein a compound of Formula 4 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:        -   n is 0, 1, or 2; and        -   R³ is N(R)(R⁹), N(R)C(O), C(O)N(R), or optionally            substituted C₃-C₇ carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂            carbocyclylalkyl, C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl,            C₆-C₁₀ aryloxy, C₆-C₁₀ aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄            aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl,            heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy, or            heteroaryl-S, wherein        -   R is hydrogen or optionally substituted C₁-C₆ alkyl, and        -   R⁹ is optionally substituted C₃-C₇ carbocyclyl, C₃-C₇            carbocyclyloxy, C₄-C₁₂ carbocyclylalkyl, C₄-C₁₂            carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₆-C₁₀            aryl-S—, C₇-C₁₄ aralkoxy, heteroaryl, heteroaryloxy,            heterocyclyl, heterocyclyloxy, heterocyclylalkyl,            heterocyclylalkoxy, C₆-C₁₀ aryl-SO₂, or heteroaryl-S.

In one embodiment of a compound of Formula 4, n is 0. In one embodimentof a compound of Formula 4, n is 1. In one embodiment of a compound ofFormula 4, R³ is N(R)(R⁹). In one embodiment of a compound of Formula 4,R is methyl. In one embodiment of a compound of Formula 4, R³ isN(R)(R⁹), in which R is methyl, and R⁹ is optionally substitutedalkylphenyl or haloalkyloxyphenyl. In one embodiment of a compound ofFormula 4, R⁹ is methylphenyl (tolyl) or isopropylphenyl. In oneembodiment of a compound of Formula 4, R³ is N(R)(R⁹), in which R ismethyl, and R⁹ optionally substituted methylphenyl. In one embodiment ofa compound of Formula 4, R³ is N(R)(R⁹), in which R is methyl, and R⁹isopropylphenyl. In one embodiment of a compound of Formula 4, R⁹ istrifluoroethoxyphenyl. In one embodiment of a compound of Formula 4, R³is substituted C₆-C₁₀ aryl. In one embodiment of a compound of Formula4, R³ is substituted methylphenyl. In one embodiment of a compound ofFormula 4, R³ is substituted cycloalkyloxyphenyl. In one embodiment of acompound of Formula 4, R³ is substituted C₄-C₁₂ carbocyclylalkoxy. Inone embodiment of a compound of Formula 4, R³ iscycloalkyloxymethylphenyl. In one embodiment of a compound of Formula 4,R³ is (cyclopropylmethoxy)methylphenyl.

At least one embodiment provides a composition comprising a compound ofFormula 4. In at least one embodiment, the composition is apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a compound of Formula 4.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 4 or a composition comprising a compound ofFormula 4.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 4. Anotherembodiment provides for use of a compound of Formula 4 in a medicamentfor treating cancer or neoplastic disease. A related embodiment providesuse of a compound, composition, or pharmaceutical composition comprisingthe compound of Formula 4 in manufacture of a medicament for treatingcancer or neoplastic disease, wherein the medicament is administered toa patient in need thereof. The cancer or neoplastic disease beingtreated, or for which the medicament is manufactured, may be prostatecancer, breast cancer, bladder cancer, lung cancer, melanoma,retinoblastoma, or multiple endocrine neoplasia type 1.

DETAILED DESCRIPTION

It should be understood that this invention is not limited to theparticular methodology, protocols, and reagents, etc., described hereinand as such may vary. The terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention, which is defined solely by the claims.

All patents and other publications identified are incorporated herein byreference for the purpose of describing and disclosing, for example, themethodologies described in such publications that might be used inconnection with the present invention, but are not to providedefinitions of terms inconsistent with those presented herein. Thesepublications are provided solely for their disclosure prior to thefiling date of the present application. Nothing in this regard should beconstrued as an admission that the inventors are not entitled toantedate such disclosure by virtue of prior invention or for any otherreason. All statements as to the date or representation as to thecontents of these documents is based on information available to theapplicants and do not constitute any admission as to the correctness ofthe dates or contents of these documents.

As used herein and in the claims, the singular forms “a,” “an,” and“the” include the plural reference unless the context clearly indicatesotherwise. The term “or” is inclusive unless modified, for example, by“either.” Thus, unless context indicates otherwise, the word “or” meansa member of a particular list and any optional combination of members ofthat list. Throughout this specification, unless otherwise indicated,“comprise,” “comprises” and “comprising” are used inclusively ratherthan exclusively, so that a stated integer or group of integers mayinclude one or more other non-stated integers or groups of integers.

The term “about” when referring to a number or a numerical range meansthat the number or numerical range referred to is an approximationwithin experimental variability (or within statistical experimentalerror), and thus the number or numerical range may vary. “About” refersgenerally to ±1% of the designated value, but may allow for ±5% or ±10%of the designated value as accepted in the relevant context by one ofskill in the art. Accordingly, numbers expressing quantities or reactionconditions used herein should be understood as modified in all instancesby the term “about” unless stated to the contrary. When ranges are usedherein for physical properties, such as molecular weight, or chemicalproperties, such as chemical formulae, all combinations andsubcombinations of ranges and specific embodiments therein are intendedto be included.

Definitions

As used in the specification and appended claims, unless specifiedotherwise, the following terms have the meaning indicated below:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Hydrazino” refers to the ═N—NH₂ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, and typically having from one to fifteen carbon atoms(e.g., C₁-C₁₅ alkyl). In certain embodiments, an alkyl comprises one tothirteen carbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, analkyl comprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to five carbon atoms (e.g., C₁-C₅alkyl). In other embodiments, an alkyl comprises one to four carbonatoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkyl comprises oneto three carbon atoms (e.g., C₁-C₃ alkyl) (i.e., methyl, ethyl, orpropyl). In other embodiments, an alkyl comprises one to two carbonatoms (e.g., C₁-C₂ alkyl) (i.e., methyl or ethyl). In other embodiments,an alkyl comprises one carbon atom (e.g., C₁ alky) (methyl). In otherembodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eightcarbon atoms (e.g., C₅-C₈ alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (e.g., C₂-C₅ alkyl). In otherembodiments, an alkyl comprises two to ten carbon atoms (e.g., C₂-C₁₀alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethyl ethyl (tert-butyl), 1-pentyl(n-pentyl). The alkyl is attached to the rest of the molecule by asingle bond. Unless stated otherwise, an alkyl group may be substituted(i.e. is optionally substituted) by one or more of the followingsubstituents: halo, cyano, amino, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, OR^(a), SR^(a), OC(O)—R^(a), N(R^(a))₂, C(O)R^(a),C(O)OR^(a), C(O)N(R^(a))₂, N(R^(a))C(O)OR^(a), OC(O)—N(R^(a))₂,N(R^(a))C(O)R^(a), N(R^(a))S(O)_(t)R^(a), S(O)_(t)OR^(a), S(O)_(t)R^(a),or S(O)_(t)N(R^(a))₂, where each t is independently 1 or 2, and eachR^(a) independently represents hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond (C═C), and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms (i.e., C₂-C₈ alkenyl). In other embodiments, an alkenylcomprises two to four carbon atoms (i.e., C₂-C₄ alkenyl). The alkenyl istypically attached to the rest of the molecule by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless specified otherwiseherein, an alkenyl group is optionally substituted by one or more of thefollowing substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, OR^(a), SR^(a), OC(O)—R^(a), N(R^(a))₂, C(O)R^(a),C(O)OR^(a), C(O)N(R^(a))₂, N(R^(a))C(O)OR^(a), OC(O)—N(R^(a))₂,N(R^(a))C(O)R^(a), N(R^(a))S(O)_(t)R^(a), S(O)_(t)OR^(a), S(O)_(t)R^(a),or S(O)_(t)N(R^(a))₂, in which each t is independently 1 or 2, and eachR^(a) independently represents hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond (C≡C), having from two to twelvecarbon atoms (i.e., C₂-C₁₂ alkynyl). In certain embodiments, an alkynylcomprises two to eight carbon atoms (i.e., C₂-C₈ alkynyl). In otherembodiments, an alkynyl has two to four carbon atoms (i.e., C₂-C₄alkynyl). The alkynyl is typically attached to the rest of the moleculeby a single bond, for example, ethynyl, propynyl, butynyl, pentynyl,hexynyl, and the like. Unless specified otherwise herein, an alkynylgroup is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, OR^(a), SR^(a), OC(O)—R^(a), N(R^(a))₂, C(O)R^(a),C(O)OR^(a), C(O)N(R^(a))₂, N(R^(a))C(O)OR^(a), OC(O)—N(R^(a))₂,N(R^(a))C(O)R^(a), N(R^(a))S(O)_(t)R^(a), S(O)_(t)OR^(a), S(O)_(t)R^(a),or S(O)_(t)N(R^(a))₂, where each t is independently 1 or 2, and eachR^(a) independently represents hydrogen, alkyl, fluoroalkyl,carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from five to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin, andnaphthalene. Unless stated otherwise specifically herein, the term“aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to includearyl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, or optionally substituted aryl, aralkyl, aralkenyl,aralkynyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, or R^(b)—OR^(a),R^(b)—OC(O)—R^(a), R^(b)—OC(O)—OR^(a), R^(b)—OC(O)—N(R^(a))₂,R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), R^(b)—C(O)OR^(a), R^(b)—C(O)N(R^(a))₂,R^(b)—O—R^(c)—C(O)N(R^(a))₂, R^(b)—N(R^(a))C(O)OR^(a),R^(b)—N(R^(a))C(O)R^(a), R^(b)—N(R^(a))S(O)_(t)R^(a), R^(b)—S(O)tR^(a),R^(b)—S(O)_(t)OR^(a), or R^(b)—S(O)_(t)N(R^(a))₂, wherein each t isindependently 1 or 2, each R^(a) independently represents hydrogen,alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionallysubstituted with one or more halo groups), aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and each R^(b)independently represents a direct bond, or a straight or branched alkylor alkenyl chain, and R^(c) is a straight or branched alkyl or alkyl,and where each of the above substituents may be substituted unlessotherwise indicated.

“Aralkyl” refers to a radical of the formula R^(c)-aryl where R^(c) isan alkyl as defined above, for example, methyl, ethyl, branched orstraight chain, and the like. The alkyl part of the aralkyl radical isoptionally substituted as described above for an alkyl chain. The arylpart of the aralkyl radical is optionally substituted as described abovefor an aryl group.

“Aralkenyl” refers to a radical of the formula R^(d)-aryl where R^(d) isan alkenyl as defined above. The aryl part of the aralkenyl radical isoptionally substituted as described above for an aryl group. The alkenylchain part of the aralkenyl radical is optionally substituted as definedabove for an alkenyl group.

“Aralkynyl” refers to a radical of the formula R^(e)-aryl, where R^(e)is an alkynyl as defined above. The aryl part of the aralkynyl radicalis optionally substituted as described above for an aryl group. Thealkynyl part of the aralkynyl radical is optionally substituted asdefined above for an alkynyl group.

“Aralkoxy” refers to a radical bonded through an oxygen atom of theformula O—R^(c)-aryl, where R^(c) is an alkyl as defined above, forexample, methyl, ethyl, straight or branched alyl chain, and the like.The alkyl part of the aralkoxy radical is optionally substituted asdescribed above for an alkyl. The aryl part of the aralkoxy radical isoptionally substituted as described above for an aryl group.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl may be saturated, (i.e.,containing single C—C bonds only) or unsaturated (i.e., containing oneor more double bonds or triple bonds). A fully saturated carbocyclylradical is also referred to as “cycloalkyl.” Examples of monocycliccycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl isalso referred to as “cycloalkenyl.” Examples of monocyclic cycloalkenylsinclude, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, andcyclooctenyl. Polycyclic carbocyclyl radicals include, for example,adamantyl, norbornyl (i.e., bicyclo(2.2.1)heptanyl), norbornenyl,decalinyl, 7,7-dimethyl-bicyclo(2.2.1)heptanyl, and the like. Unlessotherwise specified herein, “carbocyclyl” includes carbocyclyl radicalsthat are optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, or optionally substituted aryl, aralkyl,aralkenyl, aralkynyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, or R^(b)—OR^(a),R^(b)—OC(O)—R^(a), R^(b)—OC(O)—OR^(a), R^(b)—OC(O)—N(R^(a))₂,R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), R¹—C(O)OR^(a), R^(b)—C(O)N(R^(a))₂,R^(b)—O—R^(c)—C(O)N(R^(a))₂, R^(b)—N(R^(a))C(O)OR^(a),R^(b)—N(R^(a))C(O)R^(a), R^(b)—N(R^(a))S(O)_(t)R^(a),R^(b)—S(O)_(t)R^(a), R^(b)—S(O)_(t)OR^(a), or R^(b)—S(O)_(t)N(R^(a))₂,wherein each t is independently 1 or 2, where each R^(a) independentlyrepresents hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl, and where each R^(b) independently represents directbond or a straight or branched alkyl or alkenyl chain, and R^(c) is astraight or branched alkyl or alkenyl chain, and where each of the abovesubstituents may be substituted unless otherwise indicated.

“Carbocyclylalkyl” refers to a radical of the formula R^(c)-carbocyclylwhere R^(c) is an alkyl chain as defined above. The alkyl chain and thecarbocyclyl radical are optionally substituted as defined above.

“Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-carbocyclyl where R^(c) is an alkyl chain asdefined above. The alkyl chain and the carbocyclyl radical areoptionally substituted as defined above.

“Halo” or “halogen” refers to bromo, chloro, fluoro, or iodosubstituents.

“Fluoroalkyl” refers to an alkyl radical, as defined above (substitutedby one or more fluoro radicals, as defined above), for example,trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical may be optionally substituted as defined above foran alkyl group.

“Heterocyclyl” refers to a stable three- to eighteen-memberednon-aromatic ring radical that comprises two to twelve carbon atoms andfrom one to six heteroatoms (i.e., atoms other than carbon) selectedfrom nitrogen, oxygen, and sulfur. Unless specified otherwise, theheterocyclyl radical is typically a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, that may include fused or bridged ring systems.The heteroatoms in the heterocyclyl radical may be optionally oxidized.One or more nitrogen atoms, if present, are optionally quaternized. Theheterocyclyl radical may be partially or fully saturated. Theheterocyclyl may be attached to the rest of the molecule through anyatom of the ring(s). Examples of such heterocyclyl radicals include, butare not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydro-pyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxothiomorpholinyl.

Unless stated otherwise, the term “heterocyclyl” includes heterocyclylradicals as defined above that are optionally substituted by one or moresubstituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,oxo, thioxo, cyano, nitro, optionally subsitituted aryl, aralkyl,aralkenyl, aralkynyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, or R^(b)—OR^(a),R^(b)—OC(O)—R^(a), R^(b)—OC(O)—OR^(a), R^(b)—OC(O)—N(R^(a))₂,R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), R^(b)—C(O)OR^(a), R^(b)—C(O)N(R^(a))₂,R^(b)—O—R^(c)C(O)N(R^(a))₂, R^(b)—N(R^(a))C(O)OR^(a),R^(b)—N(R^(a))C(O)R^(a), R^(b)—N(R^(a))S(O)_(t)R^(a),R^(b)—S(O)_(t)R^(a), R^(b)—S(O)_(t)OR^(a), or R^(b)—S(O)_(t)N(R^(a))₂,in which each t is independently 1 or 2, wherein each R^(a)independently represents hydrogen, alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, and wherein each R^(b) independentlyrepresents a direct bond or a straight or branched alkyl or alkenylchain, and wherein R^(c) is a straight or branched alkyl or alkenylchain, and wherein each of the above substituents is unsubstitutedunless otherwise indicated.

“N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one nitrogen, and where thepoint of attachment of the heterocyclyl radical to the rest of themolecule is through a nitrogen atom in the heterocyclyl radical. AnN-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such N-heterocyclyl radicals include1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,pyrazolidinyl, imidazolinyl, and imidazolidinyl.

“C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclylradical as defined above containing at least one heteroatom and wherethe point of attachment of the heterocyclyl radical to the rest of themolecule is through a carbon atom in the heterocyclyl radical. AC-heterocyclyl radical is optionally substituted as described above forheterocyclyl radicals. Examples of such C-heterocyclyl radicals include2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or3-pyrrolidinyl, and the like.

“Heterocyclylalkyl” refers to a radical of the formulaR^(c)-heterocyclyl where R^(c) represents an alkyl as defined above. Ifthe heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclylis optionally attached to the alkyl radical at the nitrogen atom. Thealkyl of the heterocyclylalkyl radical is optionally substituted asdefined above for an alkyl. The heterocyclyl part of theheterocyclylalkyl radical is optionally substituted as defined above fora heterocyclyl group.

“Heterocyclylalkoxy” refers to a radical bonded through an oxygen atomof the formula O—R^(c)-heterocyclyl where R^(c) is an alkyl chain asdefined above. If the heterocyclyl is a nitrogen-containingheterocyclyl, the heterocyclyl is optionally attached to the alkylradical at the nitrogen atom. The alkyl of the heterocyclylalkoxyradical is optionally substituted as defined above for an alkyl. Theheterocyclyl part of the heterocyclylalkoxy radical is optionallysubstituted as defined above for a heterocyclyl group.

“Heteroaryl” refers to a radical derived from a three- toeighteen-membered aromatic ring radical that comprises two to seventeencarbon atoms and from one to six heteroatoms typically nitrogen, oxygen,or sulfur. A heteroaryl radical may be a monocyclic, bicyclic, tricyclicor tetracyclic ring system, wherein at least one of the rings in thering system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Example heteroaryls include azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydro-benzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta-[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexa-hydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoaze-pinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octa-hydrobenzo[h]quinazolinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido-[3,2-d]pyrimidinyl,pyrido[3,4-d]pyr-imidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquino-linyl,tetrahydroquinolinyl, 5,6,7,8-tetrahydro-quinazolinyl,5,6,7,8-tetrahydrobenzo-[4,5]thieno-[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno-[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless specificied otherwise herein, the term “heteroaryl”includes heteroaryl radicals as defined above which are optionallysubstituted by one or more substituents selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, haloalkenyl, halo-alkynyl, oxo, thioxo,cyano, nitro, optionally substituted aryl, aralkyl, aralkenyl,aralkynyl, carbocyclyl, carbocyclylalkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, or R^(b)—OR^(a),R^(b)—OC(O)—R^(a), R^(b)—OC(O)—OR^(a), R^(b)—OC(O)—N(R^(a))₂,R^(b)—N(R^(a))₂, R^(b)—C(O)R^(a), R^(b)—C(O)OR^(a), R^(b)—C(O)N(R^(a))₂,R^(b)—O—R^(c)—C(O)N(R^(a))₂, R^(b)—N(R^(a))C(O)OR^(a),R^(b)—N(R^(a))C(O)R^(a), R^(b)—N(R^(a))S(O)_(t)R^(a),R^(b)—S(O)_(t)R^(a), R^(b)—S(O)_(t)OR^(a), or R^(b)—S(O)_(t)N(R^(a))₂,in which each t is independently 1 or 2, in which each R^(a)independently represents hydrogen, alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl, and in which each R^(b) independentlyrepresents a direct bond or a straight or branched alkyl or alkenyl, andin which R^(c) represents a straight or branched alkyl or alkenyl, andwherein unless otherwise indicated each of the above substituents may besubstituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula R^(c)-heteroaryl,where R^(c) is an alkyl as defined above. If the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl is optionally attached tothe alkyl radical at the nitrogen atom. The alkyl of the heteroarylalkylradical is optionally substituted as defined above for an alkyl chain.The heteroaryl part of the heteroarylalkyl radical is optionallysubstituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula O—R^(c)-heteroaryl, where R^(c) is an alkyl as definedabove. If the heteroaryl is a N-containing heteroaryl, the heteroaryl isoptionally attached to the alkyl radical at the N atom. The alkyl of theheteroarylalkoxy radical is optionally substituted as defined above foran alkyl chain. The heteroaryl part of the heteroarylalkoxy radical isoptionally substituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological or chemicalproperties as a carboxylic acid moiety. Examples of carboxylic acidbioisosteres include, but are not limited to,

and the like.

The compounds described herein (which includes their pharmaceuticallyacceptable salts), in some instances contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R) or (S). When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,these compounds include both E and Z geometric isomers (e.g., cis ortrans) unless specified otherwise; likewise, all possible isomers, aswell as their racemic and optically pure forms, and all tautomeric formsare included in the compounds of the present embodiments unlessspecified otherwise. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The discussion provided hereinencompasses the various stereoisomers and mixtures thereof, and includes“enantiomers,” which refers to two stereoisomers whose molecularstructures are nonsuperimposeable mirror images of one another.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Thecompounds presented herein may, in certain embodiments, exist astautomers. In circumstances where tautomerization is possible, achemical equilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. In general as used herein, in a list of moieties,radicals, or substituents, the first instance of “optionallysubstituted” applies to all the members of the list as if the phrasewere repeated with each member. Accordingly, “optionally substitituedbenzene or hydroquinoline,” should be understood to mean “optionallysubstituted benzene or optionally substituted hydroquinoline.”

A “pharmaceutically acceptable salt” of any one of the compoundsdescribed herein includes any and all pharmaceutically suitable saltforms. These pharmaceutically acceptable salts are pharmaceuticallyacceptable acid addition salts or pharmaceutically acceptable baseaddition salts. Standard references for the preparation and selection ofpharmaceutical salts of the substituted pyridine and pyridazinederivative compounds are known in the art. See, e.g., Stahl & Wermuth,HANDBOOK PHARM. SALTS (Verlag Helvetica Chimica Acta, Zurich, 2002);Berge et al., Pharmaceutical Salts, 66 J. Pharm. Sci. 1-19 (1997).

A “pharmaceutically acceptable acid addition salt” retains the desirablebiological effectiveness and properties of the free base, and istypically formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.These include, for example, salts formed with organic acids such asaliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids,aliphatic and aromatic sulfonic acids, etc.; and include, for example,acetic acid, trifluoroacetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Exemplary saltsthus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfates,nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. These salts also include salts of aminoacids, such as arginates, gluconates, and galacturonates. Acid additionsalts of basic compounds may be prepared by contacting the free baseforms with a sufficient amount of the desired acid to produce the salt,according to methods and techniques well-known to those of skill in theart. See Berge et al., 1997.

A “pharmaceutically acceptable base addition salt” retains the desirablebiological effectiveness and properties of the free acids, and isprepared from addition of an inorganic base or an organic base to thefree acid. Pharmaceutically acceptable base addition salts may be formedwith metals or amines, such as alkali and alkaline earth metals, ororganic amines. Salts derived from inorganic bases include sodium,potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper,manganese, aluminum salts, and the like. Salts derived from organicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methyl-glucamine, glucosamine, methylglucamine, theo-bromine, purines,piperazine, piperidine, N-ethyl-piperidine, polyamine resins and thelike. See Berge et al., 1997.

The terms, “treatment,” “treating,” “palliating,” or “ameliorating” areused interchangeably herein, and refer to an approach for obtainingbeneficial or desired results including but not limited to therapeuticbenefit or a prophylactic benefit. By “therapeutic benefit” is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder, such that an improvement is observed inthe patient, notwithstanding that the patient may still be afflictedwith the underlying disorder. For prophylactic benefit, the compositionsmay be administered to a patient at risk of developing a particulardisease, or to a patient reporting one or more of the physiologicalsymptoms of a disease, even though a diagnosis of this disease may nothave been made.

“Prodrug” indicates a compound that may be converted under physiologicalconditions or by solvolysis to a biologically active compound describedherein. Thus, the term “prodrug” refers to a precursor of a biologicallyactive compound that is pharmaceutically acceptable. A prodrug may beinactive when administered to a subject, but is converted in vivo to anactive compound, for example, by hydrolysis. The prodrug compound mayoffer advantages of solubility, tissue compatibility, or delayed releasein a mammalian organism. See, e.g., Bundgard, DESIGN OF PRODRUGS, 7-9,21-24 (Elsevier, Amsterdam, 1985); Higuchi & Stella, Pro-drugs as NovelDelivery Systems, 14 A.C.S. Symposium Series in BIOREVERSIBLE CARRIERSIN DRUG DESIGN (Pergamon Press, 1987).

The term “prodrug” also includes any covalently bonded carriers thatrelease the active compound in vivo when such prodrug is administered toa mammalian subject. Prodrugs of an active compound, as describedherein, may be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds comprising a hydroxy, amino or mercapto groupbonded to any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino, or free mercapto group, respectively. Examples of prodrugsinclude acetate, formate and benzoate derivatives of alcohol or aminefunctional groups in the active compounds.

Throughout the discussion of the present embodiments in thisspecification, and in the claims, reference to a compound of Formula 1,Formula 2, Formula 3, Formula 4, the compounds described herein, orprovided by the embodiments hereof, and the like, includes by thisincorporation unless context specifies otherwise: a pharmaceuticallyacceptable salt, stereoisomer, prodrug, hydrate, solvate, or N-oxidethereof. Accordingly, for example, reference to “compound of Formula 1,”typically encompasses “compound of Formula 1 or a stereoisomer orpharmaceutically acceptable salt thereof” unless context requiresotherwise.

Substituted Pyridine Derivative Compounds

The embodiments of substituted pyridine derivative compounds describedherein inhibit at least one histone demethylase enzyme. These compounds,and compositions comprising these compounds, are useful for thetreatment of cancer and neoplastic disease. For example, embodiments ofthe compounds described herein are useful for treating prostate cancer,breast cancer, bladder cancer, lung cancer, or melanoma, and the like.

At least one embodiment provides a compound having the structure ofFormula 1:

-   -   wherein a compound of Formula 1 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:    -   n is 0, 1, or 2;    -   R⁴ is hydrogen or optionally substituted C₁-C₆ alkyl;    -   R⁶ is hydrogen or X—Y, wherein        -   X is a bond, O, S, N(R), C(O), N(R)C(O), C(O)N(R), or            optionally substituted C₁-C₃ alkyl,            -   in which R is hydrogen or optionally substituted C₁-C₆                alkyl, and        -   Y is optionally substituted alkyl, cycloalkyl, heterocyclyl,            aryl, or heteroaryl; and    -   R⁵, R⁷, and R⁸ are each independently selected from hydrogen,        halogen, hydroxyl, cyanyl, N(R¹)(R²), or optionally substituted        C₁-C₆ alkyl, C₁-C₆ alkynyl, C₁-C₆ alkenyl, C₁-C₆ alkoxy, C₃-C₇        carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂ carbocyclylalkyl,        C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₆-C₁₀        aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄ aralkoxy, heteroaryl,        heteroaryloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl,        heterocyclylalkoxy or heteroaryl-S, wherein        -   R¹ is hydrogen or optionally substituted alkyl, and        -   R² is optionally substituted alkyl, aryl, heteroaryl,            heterocyclyl, cycloalkyl, alkylalkoxy, heteroarylalkoxy,            cycloalkylalkoxy, cycloalkylalkyl, aryl-CO, heteroaryl-CO,            cycloalkyl-CO, or alkyl-CO.

In at least one embodiment of a compound of Formula 1, n is 0. In atleast one embodiment of a compound of Formula 1, n is 1. In at least oneembodiment of a compound of Formula 1, n is 0. In at least oneembodiment of a compound of Formula 1, n is 2.

At least one embodiment provides a compound of Formula 1 wherein R⁴ isoptionally substituted C₁-C₆ alkyl. In at least one embodiment of acompound of Formula 1, R⁴ is methyl.

In at least one embodiment of the compound of Formula 1, each of R⁵, R⁷,and R⁸ are hydrogen. Another embodiment provides the compound of Formula1 wherein each R⁵, R⁷ and R⁸ is independently hydrogen or halogen.

Another embodiment provides the compound of Formula 1 wherein X is abond. Another embodiment provides the compound of Formula 1 wherein X isO. Another embodiment provides the compound of Formula 1 wherein X is S.Another embodiment provides the compound of Formula 1 wherein X is N(R).Another embodiment provides the compound of Formula 1 wherein X is C(O).Another embodiment provides the compound of Formula 1 wherein X isN(R)C(O). Another embodiment provides the compound of Formula 1 whereinX is C(O)N(R). Another embodiment provides the compound of Formula 1wherein X is optionally substituted C₁-C₃ alkyl.

At least one embodiment provides the compound of Formula 1 wherein R ishydrogen. Another embodiment provides the compound of Formula 1 whereinR is optionally substituted C₁-C₆ alkyl. Another embodiment provides thecompound of Formula 1 wherein R is methyl.

Another embodiment provides the compound of Formula 1 wherein Y isoptionally substituted alkyl. Another embodiment provides the compoundof Formula 1 wherein Y is optionally substituted cycloalkyl. Anotherembodiment provides the compound of Formula 1 wherein Y is optionallysubstituted heterocyclyl. Another embodiment provides the compound ofFormula 1 wherein Y is optionally substituted aryl. Another embodimentprovides the compound of Formula 1 wherein Y is optionally substitutedheteroaryl.

In at least one embodiment of a compound of Formula 1 Y is N(R¹)(R²). Inat least one embodiment of a compound of Formula 1, X is a bond, and Yis N(R¹)(R²).

At least one embodiment provides the compound of Formula 1 wherein R¹ ishydrogen. Another embodiment provides the compound of Formula 1 whereinR¹ is optionally substituted alkyl. Another embodiment provides thecompound of Formula 1 wherein R¹ is methyl. In at least one embodimentof a compound of Formula 1, X is a bond, and Y is N(R¹)(R²) in which R¹is methyl and R² is substituted aryl.

In particular embodiments of compound Formula 1, n is 0, R⁴ is methyl,and each of R⁵, R⁷, and R⁸ are hydrogen. In some embodiments of acompound Formula 1, n is 1, R⁴ is methyl, and each of R⁵, R⁷, and R⁸ arehydrogen. In particular embodiments of compound of Formula 1 n is 0; R⁴is methyl; each of R⁵, R⁷, and R⁸ is hydrogen; and R⁶ is X—Y, wherein Xis a bond, and Y is either (a) N(R)(R⁹) wherein R is methyl and R⁹ isoptionally substituted aryl or heterocyclyl, or (b) optionallysubstituted aryl, heterocyclyl, aryloxy, or aryl-S. In a particularembodiment in which Y is (N(R¹)(R⁹), R is methyl and R⁹ is tolyl. Tolylcan be, for example, para-tolyl or ortho-tolyl. In other particularembodiments of compound Formula 1, n is 1; R⁴ is hydrogen; each of R⁵,R⁷ and R⁸ is hydrogen; and R⁶ is X—Y in which X is a bond and Y iseither (a) N(R)(R⁹) wherein R¹ is methyl and R⁹ is optionallysubstituted aryl or heterocyclyl, or (b) optionally substituted aryl,heterocyclyl, aryloxy, or aryl-S.

An aspect of the present embodiments provides a composition comprising acompound of Formula 1. In at least one embodiment, the composition is apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a compound of Formula 1.

Another aspect of the present embodiments provides a method ofinhibiting a histone demethylase enzyme comprising contacting thehistone demethylase enzyme with a compound of Formula 1 or a compositioncomprising a compound of Formula 1.

Another aspect of the present embodiments provides a method of treatingcancer in a subject in need thereof, comprising administering to thesubject a pharmaceutical composition comprising a compound of Formula 1.A related embodiment provides a method of treating cancer in a subjectin need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 1. A relatedembodiment provides use of a compound, composition, or pharmaceuticalcomposition comprising the compound of Formula 1 in manufacture of amedicament for treating cancer or neoplastic disease, wherein themedicament is administered to a patient in need thereof. The cancer orneoplastic disease being treated, or for which the medicament ismanufactured, may be prostate cancer, breast cancer, bladder cancer,lung cancer, melanoma, retinoblastoma, or multiple endocrine neoplasiatype 1.

At least one embodiment provides a compound of Formula 2:

-   -   wherein a compound of Formula 2 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:        -   n is 0, 1, or 2;        -   R⁴ is hydrogen or optionally substituted C₁-C₆ alkyl; and        -   R³ is N(R)(R⁹), N(R)C(O), C(O)N(R), or optionally            substituted C₃-C₇ carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂            carbocyclylalkyl, C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl,            C₆-C₁₀ aryloxy, C₆-C₁₀ aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄            aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl,            heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy or            heteroaryl-S, wherein        -   R is hydrogen or optionally substituted C₁-C₆ alkyl, and        -   R⁹ is optionally substituted C₃-C₇ carbocyclyl, C₃-C₇            carbocyclyloxy, C₄-C₁₂ carbocyclylalkyl, C₄-C₁₂            carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₆-C₁₀            aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄ aralkoxy, heteroaryl,            heteroaryloxy, heterocyclyl, heterocyclyloxy,            heterocyclylalkyl, heterocyclylalkoxy or heteroaryl-S.

In at least one embodiment of a compound of Formula 2, n is 0. In atleast one embodiment of a compound of Formula 2, n is 1.

In at least one embodiment of a compound of Formula 2, R⁴ is methyl. Inat least one embodiment of a compound of Formula 2, R⁴ is H. In at leastone embodiment of a compound of Formula 2, R⁴ is C₂ alkyl. In at leastone embodiment of a compound of Formula 2, R⁴ is C₃ alkyl. In at leastone embodiment of a compound of Formula 2, R⁴ is C₄ alkyl.

In at least one embodiment of a compound of Formula 2, R³ is N(R)(R⁹).In at least one embodiment of a compound of Formula 2 in which R³ isN(R)(R⁹), R and R⁴ are independently H or methyl.

In n some embodiments of a compound of Formula 2, R⁹ is optionallysubstituted haloaryl, such as chlorophenyl, fluorophenyl,difluorophenyl, or fluorochlorophenyl. In some of these embodiments, Rand R⁴ may be chosen independently from hydrogen or methyl.

In some embodiments of a compound of Formula 2, R⁹ is optionallysubstituted alkylaryl, such as methylphenyl (“tolyl”), ethylphenyl (suchas 2-ethylphenyl), n-proplyphenyl (such as 4-n-propylphenyl),isopropylphenyl (such as 2- or 4-isopropylphenyl), pentylphenyl,hexylphenyl, cyclohexylphenyl, cyclobutylmethylphenyl, orcyclopropylmethylphenyl. In some embodiments of a compound of Formula 2,R⁹ is optionally substituted 2-tolyl (o-tolyl), or 4-tolyl (p-tolyl). Insome of these embodiments, R and R⁴ may independently be chosen fromhydrogen or methyl.

In some embodiments of a compound of Formula 2, R³ is N(R)(R⁹) in whichR⁹ is optionally substituted alkyloxyphenyl, such astrifluoroethoxyphenyl. In some embodiments of a compound of Formula 2,R⁹ is optionally substituted trifluoroethylphenyl ortrifluoroethoxy-phenyl, such as trifluoroethoxy-methylphenyl or(trifluoroethoxy)fluorophenyl. In these embodiments, R and R⁴ mayindependently be chosen from hydrogen or methyl.

In some embodiments in which R³ is N(R)(R⁹), R⁹ is heterocyclylaryl,such as pyranylphenyl. In some of these embodiments, R and R⁴ mayindependently be chosen from hydrogen or methyl.

In at least one embodiment of a compound of Formula 2, R³ is N(R)(R⁹) inwhich R is methyl and R⁹ is propylphenyl or isopropylphenyl. In anembodiment of a compound of Formula 2, R³ is N(R)(R⁹) in which R ismethyl and R⁹ is trifluoroethoxyphenyl. In particular embodiments of acompound of Formula 2, R³ is N(R)(R⁹), R is methyl, and R⁹ is optionallysubstituted methylphenyl. In particular embodiments of Formula 2, R³ isN(R)(R⁹), R is methyl, and R⁹ is isopropylphenyl. In particularembodiments of a compound of Formula 2, R³ is N(R)(R⁹), R is methyl, andR⁹ is optionally substituted halophenyl, alkylphenyl, haloalkylphenyl,halo(alkyloxy)phenyl, or haloalkyloxyphenyl. In an embodiment of acompound of Formula 2, R³ is N(R)(R⁹), R is methyl, and R⁹ is optionallysubstituted alkylphenyl or haloalkyloxyphenyl. In an embodiment of acompound of Formula 2, R³ is N(R)(R⁹), R is methyl, and R⁹ is tolyl.Tolyl, in particular embodiments of Formula 2, is p-tolyl or o-tolyl. Insome of these embodiments, R and R⁴ may independently be hydrogen ormethyl.

In at least one embodiment, R³ is optionally substituted aminophenyl.For example, the amino radical may be N(R)₂, wherein R is methyl. Insome of these embodiments, R and R⁴ may independently be hydrogen ormethyl.

In particular embodiments of a compound of Formula 2 in which R³ isN(R)(R⁹), R⁹ is selected from chlorophenyl, difluorophenyl,chlorofluorophenyl, (trifluoroethyl)phenyl, (trifluoropropyl)phenyl,methylphenyl (tolyl), dimethylphenyl, ethylphenyl, propylphenyl,butylphenyl, pentylphenyl, hexylphenyl, (cyclopropylethyl)phenyl,cyclopropylphenyl, cyclobutylphenyl, cyclopentylphenyl,cyclohexylphenyl, (cyclobutylmethyl)phenyl, propoxyphenyl,(propylmethoxy)phenyl, (trifluoroethoxy)phenyl,(trifluoroethoxy)fluorophenyl, (trifluoroethoxy)dimethylphenyl,(propoxy)methylphenyl, (difluoromethoxy)methylphenyl,(quinolinyl)methyl-phenyl, (dihydroquinolinyl)methylphenyl,indolinylphenyl, dimethylaminophenyl, pyranylphenyl,methyldihydrobenzofuranyl, (indolinyl)methylphenyl,(pyrrolidinyl)methylphenyl, or thiole. In some of these embodiments, Rand R⁴ may be independently hydrogen or methyl.

In some embodiments of a compound of Formula 2 in which R³ is N(R)(R⁹),R is optionally substituted C₂-C₄ alkyl; for example R may be ethyl,cyclopropylmethyl, or trifluroethyl. In such embodiments of a compoundof Formula 2, R⁹ may be any substitutent as described herein for acompound of Formula 2. For example, when R³ is N(R)(R⁹) and R is ethyl,cyclopropylmethyl or trifluroethyl, R⁹ may be tolyl. In some of theseembodiments, R⁴ may be hydrogen or methyl.

In at least one embodiment of a compound of Formula 2, R³ is optionallysubstituted aryl, alkylphenyl, alkoxyphenyl, cyclyloxyphenyl,aryloxyphenyl, heterocyclylphenyl, or heterocyclylalkylphenyl. In someof these embodiments, R⁴ may be hydrogen or methyl.

For example, optionally substituted aryl can be optionally substitutedhaloaryl, such as optionally substituted fluorophenyl; or can bealklyaryl, such as optionally substituted methylphenyl. In someembodiments of a compound of Formula 2, R³ is substituted C₆-C₁₀ aryl.In some embodiments of Formula 2, R³ is optionally substituted mono-,di-, or tri-halophenyl. In some embodiments of Formula 2, R³ isoptionally substituted fluorophenyl, difluorophenyl (e.g.,2,4-difluorophenyl), chlorofluorophenyl, or chlorodifluorophenyl. In oneembodiment of a compound of Formula 2, R³ is (methoxy)fluorophenyl. Insome embodiments of Formula 2, R³ is an optionally substitutedhaloalkylaryl such as (trifluoroethyl)methylphenyl or(trifluoroethyl)-dimethylphenyl. In one embodiment of Formula 2, R³ isan optionally substituted haloalkyloxyaryl such as(trifluoroethoxy)methylphenyl. In one embodiment of Formula 2, R³ is(trifluoroethoxy)-halophenyl, such as (trifluoroethoxy)fluorophenyl. Insome of these embodiments, R⁴ may be hydrogen or methyl.

In at least one embodiment of a compound of Formula 2, R³ is optionallysubstituted alkylphenyl. In some embodiments of a compound of Formula 2,R³ is optionally substituted methylphenyl (such as 2- or 4-methylphenyl)or dimethylphenyl (such as 2,4-dimethylphenyl). In at least oneembodiment of a compound of Formula 2, R³ is ethylphenyl (such as 2- or4-ethylphenyl) or propylphenyl (such as 2- or 4-iso- orcyclo-propylphenyl). In some embodiments of a compound of Formula 2, R³is (isopropyl)methylphenyl or (n-propyl)-methylphenyl. In someembodiments of a compound of Formula 2, R³ is a substitutedmethylphenyl, such as (methoxy)methylphenyl, (ethoxy)methylphenyl,(propoxy)methylphenyl, (isopropoxy)methylphenyl,(trifluoroethoxy)methylphenyl, (phenoxy)methylphenyl,(pyrrolidin)methylphenyl. In some of these embodiments, R⁴ may behydrogen or methyl.

In some embodiments, R³ is optionally substituted alkyloxyphenyl, suchas methoxy-isopropylphenyl. In one embodiment of a compound of Formula2, R³ is optionally substituted (cycloalkyloxy)phenyl. In one embodimentof a compound of Formula 2, R³ is substituted C₄-C₁₂ carbocyclylalkoxy,such as (cycloalkyloxy)methylphenyl, such as, for example,(cyclopropyl-methoxy)methylphenyl, (cyclobutylmethoxy)methylphenyl, or(cyclopentylmethoxy)methylphenyl. In one embodiment of a compound ofFormula 2, R³ is substituted alkaryloxyaryl, such as(methyl-phenoxy)phenyl. In some of these embodiments, R⁴ may be hydrogenor methyl.

In some embodiments of Formula 2, R³ is optionally substitutedheterocyclylalkylphenyl, such as (dihydroquinolinyl)methylphenyl, or(pyrrolidinyl)methylphenyl. In these embodiments, R⁴ may be hydrogen ormethyl.

In at least one embodiment of Formula 2, R³ is optionally substitutedheterocyclyl or heteroaryl. In some embodiments of Formula 2, R³ isoptionally substituted thiophenyl or thiole, indolinyl, or quinolinyl.Example embodiments of substituted lindolinyl are methylindolinyl andbiisoquinolinyl. In some embodiments of Formula 2, R³ is optionallysubstituted dihydrobenzofuranyl or methyldihydrobenzofuranyl. In some ofthese embodiments, R⁴ may be hydrogen or methyl.

In at least one embodiment of Formula 2, R³ is optionally substitutedC₆-C₁₀ aryloxy, such as halophenoxy, for example fluorophenoxy (e.g., 2-or 4-fluorophenoxy); or C₆-C₁₀ alkylaryloxy, for example tolyloxy. Inthese embodiments, R⁴ may be hydrogen or methyl.

In at least one embodiment, R³ is heterocyclyl- orheterobicyclyl-methylphenyl; for example quinolin methylphenyl, inparticular 6-(3,4-dihydroquinolin)methylphenyl, or4(3,4-dihydroquinolin)-methylphenyl. In at least one embodiment, R³ isheterocyclyloxy- or heterobicyclyloxy-methylphenyl (e.g.,phenoxyphenyl). In at least one embodiment, R³ is(pyrrolidinyl)methylphenyl. In some of these embodiments, R⁴ may behydrogen or methyl.

In at least one embodiment of Formula 2, R³ is optionally substitutedC₆-C₁₀ aryl-S, such as an alkylaryl-S, for example tolylthio (e.g., p-or o-tolylthio). In at least one embodiment of Formula 2, R³ isoptionally substituted C₆-C₁₀ aryl-S, such as an halolaryl-S, forexample 2- or 4-fluorophenylthio. In one embodiment of Formula 2, R³ isoptionally substituted C₆-C₁₀ arylsulfanyl, such as tolylthio (ortolylsulfanyl) or fluorophenylthio. In some of these embodiments, R⁴ maybe hydrogen or methyl.

In particular embodiments of a compound of Formula 2, R³ is selectedfrom chlorophenyl, difluorophenyl, chlorofluorophenyl,(trifluoroethyl)phenyl, (trifluoropropyl)-phenyl, methylphenyl(“tolyl”), dimethylphenyl, ethylphenyl, propylphenyl (such asisopropylphenyl), butylphenyl, pentylphenyl, hexylphenyl,cyclopropylphenyl, cyclobutylphenyl, cyclopentylphenyl,cyclohexylphenyl, (cyclopropylethyl)phenyl, (cyclobutylmethyl)phenyl,propoxyphenyl, (propylmethoxy)phenyl, (trifluoroethoxy)phenyl,(trifluoroethoxy)fluorophenyl, (trifluoroethoxy)dimethylphenyl,(propoxy)methylphenyl, (difluoromethoxy)methylphenyl,(quinolinyl)-methylphenyl, (dihydroquinolinyl)methylphenyl,indolinylphenyl, dimethylaminophenyl, pyranyl-phenyl,methyldihydrobenzofuranyl, (indolinyl)methylphenyl,(pyrrolidinyl)methylphenyl, or thiole. In these embodiments, R⁴ may behydrogen or methyl.

In particular embodiments of the compound of Formula 2, the compound is(R) or (S)3-[((6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl)methyl)amino]pyridine-4-carboxylicacid; (R) or (S)3-([(6-(methyl[4-(methylethyl)phenyl]amino)-1,2,3,4-tetrahydroiso-quinolyl)methyl]amino)pyridine-4-carboxylicacid; (R) or (S) 3-[((5-[methyl(4-methylphenyl)-amino]isoindolinyl)methyl)amino]pyridine-4-carboxylicacid; (R) or (S)3-([(6-(methyl[4-(methyl-ethyl)phenyl]amino)-1,2,3,4-tetrahydroisoquinolyl)methyl]amino)pyridine-4-carboxylic acid; (R) or (S)3-(((2-methyl-5-(methyl(p-tolyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R) or (S)3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)-amino)isonicotinicacid; (R) or (S)3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (R) or (S)3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinicacid; (R) or (S)3-(((2-methyl-5-(methyl(p-tolyl)amino)isoindolin-1-yl)methyl)amino)isonicotinicacid; (R) or (S)3-(((5-((4-ethyl-phenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinicacid; (R) or (S)3-(((2-methyl-5-(methyl(4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinicacid; (R) or (S)3-(((2-methyl-5-(o-tolyl)iso-indolin-1-yl)methyl)amino)isonicotinicacid; or (R) or (S)3-(((5-(2-ethylphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinicacid. In these embodiments, R⁴ may be hydrogen or methyl.

In some embodiments of Formula 2, n is 2. In some embodiments of Formula2 wherein n is 2, R³ and R⁴ may be as described above. In some of theseembodiments, R and R⁴ may be independently hydrogen or methyl.

In at least one embodiment of a compound of Formula 2, R⁴ is C₂ alkyl(ethyl). In at least one embodiment of a compound of Formula 2, R⁴ is C₃alkyl, such as n-propyl, isopropyl, or cyclopropyl. In at least oneembodiment of a compound of Formula 2, R⁴ is C₄ alkyl, such ascyclopropylmethyl. In embodiments, where R⁴ is C₂-C₄ alkyl, R³ may beany substitutent as described above for a compound of Formula 2. Inparticular embodiments, R⁴ is ethyl and R³ is tolyl or fluoro. Inparticular embodiments, R⁴ is isopropanol or cyclopropyl and R³ is tolylor fluoro. In particular embodiments, R⁴ is cyclopropylmethyl and R³ istolyl or fluoro.

At least one embodiment provides a composition comprising a compound ofFormula 2. In at least one embodiment, the composition is apharmaceutical composition, which comprises at least onepharmaceutically acceptable excipient and a compound of Formula 2.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 2 or a composition comprising a compound ofFormula 2.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 2. A relatedembodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a pharmaceuticalcomposition comprising a compound of Formula 2. A related embodimentprovides use of a compound, composition, or pharmaceutical compositioncomprising the compound of Formula 2 in manufacture of a medicament fortreating cancer or neoplastic disease, wherein the medicament isadministered to a patient in need thereof. The cancer or neoplasticdisease being treated, or for which the medicament is manufactured, maybe prostate cancer, breast cancer, bladder cancer, lung cancer,melanoma, retinoblastoma, or multiple endocrine neoplasia type 1.

At least one embodiment provides a compound having the structure ofFormula 3:

-   -   wherein a compound of Formula 2 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:    -   n is 0, 1, or 2;    -   R⁶ is X—Y, wherein        -   X is a bond, O, S, N(R), C(O), N(R)C(O), C(O)N(R), or            optionally substituted C₁-C₃ alkyl,        -   in which R is hydrogen or optionally substituted alkyl, and        -   Y is optionally substituted alkyl, cycloalkyl, heterocyclyl,            aryl, or heteroaryl; and    -   R⁵, R⁷, and R⁸ are each independently selected from hydrogen,        halogen, hydroxyl, cyanyl, or N(R¹)(R²), or optionally        substituted C₁-C₆ alkyl, C₁-C₆ alkynyl, C₁-C₆ alkenyl, C₁-C₆        alkoxy, C₃-C₇ carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂        carbocyclylalkyl, C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀        aryloxy, C₆-C₁₀ aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄ aralkoxy,        heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy,        heterocyclylalkyl, heterocyclylalkoxy, or heteroaryl-S, in which        -   R¹ is hydrogen or optionally substituted alkyl, and        -   R² is optionally substituted alkyl, aryl, heteroaryl,            heterocyclyl, cycloalkyl, cycloalkylalkyl, aryl-CO,            heteroaryl-CO, cycloalkyl-CO, or alkyl-CO.

In one embodiment of a compound of Formula 3, n is 0. In one embodimentof a compound of Formula 3, n is 1. In one embodiment of the compound ofFormula 3, each of R⁵, R⁷, and R⁸ are hydrogen.

At least one embodiment provides a composition comprising a compound ofFormula 3. In at least one embodiment, a composition comprising acompound of Formula 3 is a pharmaceutical composition, which includes atleast one pharmaceutically acceptable excipient.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 3 or a composition comprising Formula 3 thatmay be a pharmaceutical composition.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 3. A relatedembodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a pharmaceuticalcomposition comprising a compound of Formula 3. A related embodimentprovides use of a compound, composition, or pharmaceutical compositioncomprising the compound of Formula 3 in manufacture of a medicament fortreating cancer or neoplastic disease, wherein the medicament isadministered to a patient in need thereof. The cancer or neoplasticdisease being treated, or for which the medicament is manufactured, maybe prostate cancer, breast cancer, bladder cancer, lung cancer,melanoma, retinoblastoma, or multiple endocrine neoplasia type 1.

At least one embodiment provides a compound of Formula 4:

-   -   wherein a compound of Formula 4 includes isomers and        pharmaceutically acceptable salts thereof, and wherein:        -   n is 0, 1, or 2; and        -   R³ is N(R)(R⁹), N(R)C(O), C(O)N(R), or optionally            substituted C₃-C₇ carbocyclyl, C₃-C₇ carbocyclyloxy, C₄-C₁₂            carbocyclylalkyl, C₄-C₁₂ carbocyclylalkoxy, C₆-C₁₀ aryl,            C₆-C₁₀ aryloxy, C₆-C₁₀ aryl-S, C₆-C₁₀ aryl-SO₂, C₇-C₁₄            aralkoxy, heteroaryl, heteroaryloxy, heterocyclyl,            heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy, or            heteroaryl-S, wherein        -   R is hydrogen or optionally substituted C₁-C₆ alkyl, and        -   R⁹ is optionally substituted C₃-C₇ carbocyclyl, C₃-C₇            carbocyclyloxy, C₄-C₁₂ carbocyclylalkyl, C₄-C₁₂            carbocyclylalkoxy, C₆-C₁₀ aryl, C₆-C₁₀ aryloxy, C₆-C₁₀            aryl-S—, C₇-C₁₄ aralkoxy, heteroaryl, heteroaryloxy,            heterocyclyl, heterocyclyloxy, heterocyclylalkyl,            heterocyclylalkoxy, C₆-C₁₀ aryl-SO₂, or heteroaryl-S.

In one embodiment of a compound of Formula 4, n is 0. In one embodimentof a compound of Formula 4, n is 1. In one embodiment of a compound ofFormula 4, R³ is N(R)(R⁹). In one embodiment of a compound of Formula 4,R is methyl. In one embodiment of a compound of Formula 4, R³ isN(R)(R⁹), in which R is methyl, and R⁹ is optionally substitutedalkylphenyl or haloalkyloxyphenyl. In one embodiment of a compound ofFormula 4, R⁹ is methylphenyl (tolyl) or isopropylphenyl. In oneembodiment of a compound of Formula 4, R³ is N(R)(R⁹), in which R ismethyl, and R⁹ optionally substituted methylphenyl. In one embodiment ofa compound of Formula 4, R³ is N(R)(R⁹), in which R is methyl, and R⁹isopropylphenyl. In one embodiment of a compound of Formula 4, R⁹ istrifluoroethoxyphenyl. In one embodiment of a compound of Formula 4, R³is substituted C₆-C₁₀ aryl. In one embodiment of a compound of Formula4, R³ is substituted methylphenyl. In one embodiment of a compound ofFormula 4, R³ is substituted cycloalkyloxyphenyl. In one embodiment of acompound of Formula 4, R³ is substituted C₄-C₁₂ carbocyclylalkoxy. Inone embodiment of a compound of Formula 4, R³ iscycloalkyloxymethyl-phenyl. In one embodiment of a compound of Formula4, R³ is (cyclopropylmethoxy)methylphenyl. Unless otherwise specified,the R³ and R⁹ substituents of a compound of Formula 4 include thosedescribed for Formula 2.

At least one embodiment provides a composition comprising a compound ofFormula 4. In at least one embodiment, the composition is apharmaceutical composition comprising at least one pharmaceuticallyacceptable excipient and a compound of Formula 4.

At least one embodiment provides a method of inhibiting a histonedemethylase enzyme comprising contacting the histone demethylase enzymewith a compound of Formula 4 or a composition comprising a compound ofFormula 4.

At least one embodiment provides a method of treating cancer in asubject in need thereof, comprising administering to the subject apharmaceutical composition comprising a compound of Formula 4. A relatedembodiment provides a method of treating cancer in a subject in needthereof, comprising administering to the subject a pharmaceuticalcomposition comprising a compound of Formula 4. A related embodimentprovides use of a compound, composition, or pharmaceutical compositioncomprising the compound of Formula 4 in manufacture of a medicament fortreating cancer or neoplastic disease, wherein the medicament isadministered to a patient in need thereof. The cancer or neoplasticdisease being treated, or for which the medicament is manufactured, maybe prostate cancer, breast cancer, bladder cancer, lung cancer,melanoma, retinoblastoma, or multiple endocrine neoplasia type 1.

In some embodiments, the substituted pyridine derivative compound asdescribed herein has the structure provided in Table 1, in which“Example” refers to the chemical synthesis example described in theExamples herein:

TABLE 1 Example Formula Name 1A

3-[({(1S)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl} methyl)amino]pyridine-4-carboxylicacid 1B

3-[({(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl} methyl)amino]pyridine-4-carboxylicacid 2A

3-[({(1S)-6-[2-methyl-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,2,3,4-tetrahydro- isoquinolyl}methyl)amino]pyridine-4-carboxylic acid 2B

3-[({(lR)-6-[2-methyl-4-(2,2,2- trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl) amino]pyridine-4-carboxylic acid 3A

3-{[(1S)-6-{methyl[4-isopropyl- phenyl]amino}-1,2,3,4-tetrahydro-isoquinolyl)methyl]amino}pyridine-4- carboxylic acid 3B

3-{[((1R)-6-{methyl[4-isopropylphenyl]amino}-1,2,3,4-tetrahydroisoquinolyl) methyl]amino}pyridine-4-carboxylicacid 4A

3-[({(1S)-6-[4-(cyclopropylmethoxy)-2- methylphenyl]-1,2,3,4-tetrahydro-isoquinolyl}methyl)amino]pyridine-4- carboxylic acid 4B

3-[({(1R)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]-1,2,3,4-tetrahydroiso- quinolyl}methyl)amino]pyridine-4-carboxylic acid 5A

3-[({(1S)-5-[methyl(4-tolyl)amino] isoindolinyl}methyl)amino]pyridine-4-carboxylic acid 5B

3-[({(1R)-5-[methyl(4-tolyl)amino] isoindolinyl}methyl)amino]pyridine-4-carboxylic acid 6A

3-{[((1S)-5-{methyl[4-isopropylphenyl]amino}isoindolinyl)methyl]amino}pyridine- 4-carboxylic acid 6B

3-{[((1S)-5-{methyl[4-isopropylphenyl]amino}isoindolinyl)methyl]amino}pyridine- 4-carboxylic acid 7A

3-[({(1S)-5-[2-methyl-4-(2,2,2-trifluoro-ethoxy)phenyl]isoindolinyl}methyl) amino]pyridine-4-carboxylic acid 7B

3-[({(1R)-5-[2-methyl-4-(2,2,2-trifluoro-ethoxy)phenyl]isoindolinyl}methyl)amino] pyridine-4-carboxylic acid 10A

(R)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinic acid 10B

(S)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 11A

(R)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinic acid 11B

(S)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 12A

(R)-3-(((2-methyl-6-(o-tolyl)-l,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 12B

(S)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 13A

(R)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1- yl)methyl)amino)isonicotinicacid 13B

(S)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin- 1-yl)methyl)amino)isonicotinicacid 14A

(R)-3-(((2-methyl-6-(methyl (4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 14B

(S)-3-(((2-methyl-6-(methyl (4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 15A

(R)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 15B

(S)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4- tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 16A

(R)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 16B

(S)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 17A

(R)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 17B

(S)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 18A

(R)-3-(((2-methyl-5-(methyl(p-tolyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 18B

(S)-3-(((2-methyl-5-(methyl(p-tolyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 19A

(R)-3-(((5-((4-ethylphenyl)(methyl) amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid 19B

(S)-3-(((5-((4-ethylphenyl)(methyl)amino)- 2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid 20A

(R)-3-(((2-methyl-5-(methyl (4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 20B

(S)-3-(((2-methyl-5-(methyl (4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 21A

(R)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinicacid 21B

(S)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinicacid 22A

(R)-3-(((5-(2-ethylphenyl)-2-methyl- isoindolin-1-yl)methyl)amino)isonicotinic acid 22B

(S)-3-(((5-(2-ethylphenyl)-2-methyl- isoindolin-1-yl)methyl)amino)isonicotinic acid 23A

3-({[(1R)-6-(thiol-3-yl)-1,2,3,4- tetrahydroisoquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid 23B

3-({[(1S)-6-(thiol-3-yl)-1,2,3,4- tetrahydroisoquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid 24A

3-({[(1R)-6-[2-fluoro-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-1-yl]methyl}amino)pyridine-4- carboxylic acid 24B

3-({[(1S)-6-[2-fluoro-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-1-yl]methyl}amino)pyridine-4- carboxylic acid 25A

3-({[(1R)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl} amino)pyridine-4-carboxylic acid 25B

3-({[(1S)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl} amino)pyridine-4-carboxylic acid 26A

(R)-3-(((6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 26B

(S)-3-(((6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 27A

(R)-3-(((6-(4-isopropoxy-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 27B

(S)-3-(((6-(4-isopropoxy-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 28A

(R)-3-(((6-(4-isopropyl-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 28B

(S)-3-(((6-(4-isopropyl-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 29A

(R)-3-(((6-(4-(difluoromethoxy)-2- methylphenyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid 29B

(S)-3-(((6-(4-(difluoromethoxy)-2- methylphenyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid 30A

(R)-3-(((6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 30B

(S)-3-(((6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 31A

(R)-3-(((6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 31B

(S)-3-(((6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 32A

(R)-3-(((6-(2-fluoro-6-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 32B

(S)-3-(((6-(2-fluoro-6-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 33A

(R)-3-(((6-(2-methyl-4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid 33B

(S)-3-(((6-(2-methyl-4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid 34A

(R)-3-(((6-(2-methyl-4-(3,4- dihydroisoquinolin-2(1H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1- yl)methyl)amino)isonicotinic acid 34B

(S)-3-(((6-(2-methyl-4-(3,4- dihydroisoquinolin-2(1H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl) methyl)amino)isonicotinic acid 35A

(R)-3-(((6-(4-isopropyl-2-methoxy-phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl) methyl)amino)isonicotinic acid 35B

(S)-3-(((6-(4-isopropyl-2-methoxy-phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl) methyl)amino)isonicotinic acid 36A

(R)-3-(((6-(2-methyl-4-(6-methyl-indolin-1-yl)phenyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid 36B

(S)-3-(((6-(2-methyl-4-(6-methyl-indolin-1-yl)phenyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid 37A

(R)-3-(((6-((4-cyclopropylphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 37B

(S)-3-(((6-((4-cyclopropylphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 38A

(R)-3-(((6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 38B

(S)-3-(((6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 39A

(R)-3-(((6-((4-isobutylphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 39B

(S)-3-(((6-((4-isobutylphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 40A

(R)-3-(((6-((4-hexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1- yl)methyl)amino)isonicotinicacid 40B

(S)-3-(((6-((4-hexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1- yl)methyl)amino)isonicotinicacid 41A

(R)-3-(((6-((4-(cyclopropylmethyl) phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 41B

(S)-3-(((6-((4-(cyclopropylmethyl) phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 42A

(R)-3-(((6-(methyl(4-(2,2,2- trifluoroethoxy)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 42B

(S)-3-(((6-(methyl(4-(2,2,2- trifluoroethoxy)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 43A

(R)-3-(((6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid 43B

(S)-3-(((6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 44A

(R)-3-(((6-((4-isopropoxyphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 44B

(S)-3-(((6-((4-isopropoxyphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 45A

(R)-3-(((6-(methyl(4-(2,2,2-trifluoro-ethyl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid 45B

(S)-3-(((6-(methyl(4-(2,2,2-trifluoro-ethyl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid 46A

(R)-3-(((6-((4-chlorophenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 46B

(S)-3-(((6-((4-chlorophenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 47A

(R)-3-(((6-(2-ethylphenyl)-1,2,3,4- tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 47B

(S)-3-(((6-(2-ethylphenyl)-1,2,3,4- tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 48A

(R)-3-(((6-(2-isopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 48B

(S)-3-(((6-(2-isopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 49A

(R)-3-(((6-(2,6-dimethyl-4-(2,2,2- trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 49B

(S)-3-(((6-(2,6-dimethyl-4-(2,2,2- trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 50A

(R)-3-(((6-(2-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 50B

(S)-3-(((6-(2-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 51A

(R)-3-(((6-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 51B

(S)-3-(((6-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid 52A

(R)-3-(((6-(2-cyclopropylphenyl)-1,2,3,4- tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 52B

(S)-3-(((6-(2-cyclopropylphenyl)-1,2,3,4- tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 53A

(R)-3-(((6-((4-(dimethylamino)phenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 53B

(S)-3-(((6-((4-(dimethylamino)phenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 54A

(R)-3-(((6-((4-cyclohexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 54B

(S)-3-(((6-((4-cyclohexylphenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 55A

(R)-3-(((6-(methyl(4-(tetrahydro-2H- pyran-4-yl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid 55B

(S)-3-(((6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino) isonicotinic acid 56A

(R)-3-(((6-(methyl(4-(3,3,3- trifluoropropyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 56B

(S)-3-(((6-(methyl(4-(3,3,3- trifluoropropyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 57A

(R)-3-(((6-((4-(2-cyclopropylethyl) phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 57B

(S)-3-(((6-((4-(2-cyclopropylethyl)phenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 58A

(R)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 58B

(S)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin- 1-yl)methyl)amino)isonicotinicacid 59A

(R)-3-(((6-((4-cyclopentylphenyl) (methyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid 59B

(S)-3-(((6-((4-cyclopentylphenyl) (methyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid 60A

(R)-3-(((6-((4-(cyclobutylmethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid 60B

(S)-3-(((6-((4-(cyclobutylmethyl)phenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid 61A

(R)-3-(((6-(6-methyl-2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid61B

(S)-3-(((6-(6-methyl-2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid62A

(R)-3-(((6-(5-methyl-2,3-dihydrobenzofuran-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid62B

(S)-3-(((6-(5-methyl-2,3-dihydrobenzofuran-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid63A

(R)-3-(((5-(2-fluoro-4-(2,2,2- trifluoroethoxy)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid 63B

(S)-3-(((5-(2-fluoro-4-(2,2,2- trifluoroethoxy)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid 64A

(R)-3-(((5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinic acid 64B

(S)-3-(((5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinic acid 65A

(R)-3-(((5-((4-isopropylphenyl)(methyl)amino)isoindolin-1-yl)methyl)amino) isonicotinic acid 65B

(S)-3-(((5-((4-isopropylphenyl)(methyl)amino)isoindolin-1-yl)methyl)amino) isonicotinic acid 66A

(R)-3-(((5-(4-isopropyl-2- methylphenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid 66B

(S)-3-(((5-(4-isopropyl-2- methylphenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid 67A

(R)-3-(((5-((4-cyclopropylphenyl) (methyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 67B

(S)-3-(((5-((4-cyclopropylphenyl) (methyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 68A

(R)-3-(((5-((4-ethylphenyl)(methyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 68B

(S)-3-(((5-((4-ethylphenyl)(methyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 69A

(R)-3-(((5-(methyl(4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 69B

(S)-3-(((5-(methyl(4-propylphenyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 70A

(R)-3-(((5-(2-methyl-4-(pyrrolidin-1-yl) phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid 70B

(S)-3-(((5-(2-methyl-4-(pyrrolidin-1-yl) phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid 71A

(R)-3-(((5-(2-ethylphenyl)isoindolin- 1-yl)methyl)amino)isonicotinicacid 71B

(S)-3-(((5-(2-ethylphenyl)isoindolin- 1-yl)methyl)amino)isonicotinicacid 72A

(R)-3-(((5-(2-isopropylphenyl)isoindolin- 1-yl)methyl)amino)isonicotinicacid 72B

(S)-3-(((5-(2-isopropylphenyl)isoindolin- 1-yl)methyl)amino)isonicotinicacid 73A

(R)-3-(((5-(2-cyclopropylphenyl) isoindolin-1-yl)methyl)amino)isonicotinic acid 73B

(S)-3-(((5-(2-cyclopropylphenyl) isoindolin-1-yl)methyl)amino)isonicotinic acid

In some embodiments, the substituted pyridine derivative compound asdescribed herein, or a stereoisomer or pharmaceutically acceptable saltthereof, has the structure provided in Table 2:

TABLE 2

(S)-3-(((6-(thiol-3-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(thiol-3-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-(difluoromethyl)-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-(difluoromethyl)-2-methyl-phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(3,4-dihydroquinolin-1(2H)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(3,4-dihydroquinolin-1(2H)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(5-methylindolin-1-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(5-methylindolin-1-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((1′,2′,3,3′,4,4′-hexahydro-1H-[2,6′-bi-isoquinolin]-1′-yl)methyl)amino)isonicotinic acid

(R)-3-(((1′,2′,3,3′,4,4′-hexahydro-1H-[2,6′-bi-isoquinolin]-1′-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-chloro-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-chloro-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-((6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methoxy)isonicotinic acid

(R)-3-((6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methoxy)isonicotinic acid

(S)-3-((6-((4-isopropylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy)isonicotinic acid

(R)-3-((6-((4-isopropylphenyl)(methyl)amino)-12,3,4-tetrahydroisoquinolin-1-yl)methoxy)isonicotinic acid

(S)-3-((6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy)isonicotinic acid

(R)-3-((6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy)isonicotinic acid

(S)-3-(((6-(p-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(p-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(o-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(o-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(p-tolylthio)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(p-tolylthio)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(o-tolylthio)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(o-tolylthio)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-((4-fluorophenyl)thio)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-((4-fluorophenyl)thio)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-((2-fluorophenyl)thio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-((2-fluorophenyl)thio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2-methyl-4-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2-methyl-4-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2,4-difluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2,4-difluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-chloro-2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-chloro-2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-methyl-4-phenoxyphenyl)isoindolin- 1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-methyl-4-phenoxyphenyl)isoindolin- 1-yl)methyl)amino)isonicotinic acid

(S)-3-(((7-(methyl(p-tolyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((7-(methyl(p-tolyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((7-((4-isopropylphenyl)(methyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((7-((4-isopropylphenyl)(methyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((7-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((7-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid

3-[({(1S)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]-1,2,3,4-tetrahydroisoquinol-yl}methyl)amino]pyridine-4-carboxylic acid

3-[({(1R)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]-1,2,3,4-tetrahydroisoquinol-yl}methyl)amino]pyridine-4-carboxylic acid

(R)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-((4-isopropylphenyl)methyl)amino-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-((4-isopropylphenyl)methyl)amino-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-((4-isopropyl-2-methylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-((4-isopropyl-2-methylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-isopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-isopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-cyclopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-cyclopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-fluoro-2-methylphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-fluoro-2-methylphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-methoxyphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-methoxyphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-fluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-fluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2,4-difluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2,4-difluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-cyclopropylmethoxy)-2-fluorophenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-cyclopropylmethoxy)-2-fluorophenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-fluoro-4-methoxyphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-fluoro-4-methoxyphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-methoxyphenyl-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-methoxyphenyl-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-(dimethylamino)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-(dimethylamino)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-(azetidin-1-yl)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-(azetidin-1-yl)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-ethyl-5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinicacid

(S)-3-(((2-ethyl-5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinicacid

(R)-3-(((2-ethyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-ethyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-isopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-isopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-cyclopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-cyclopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-cyclopropyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-cyclopropyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-fluorophenyl)-2-isopropyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-fluorophenyl)-2-isopropyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-(cyclopropylmethyl)-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-(cyclopropylmethyl)-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-5-(2-pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-5-(2-pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(2-dimethylamino)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(2-dimethylamino)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(4-isopropyl-2-methoxyphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(4-isopropyl-2-methoxyphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-5-(p-tolyloxy)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-5-(p-tolyloxy)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-5-(p-tolylthio)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-5-(p-tolylthio)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-ethyl(p-tolyl)amino)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-ethyl(p-tolyl)amino)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-5-(p-tolyl(2,2,2-trifluoroethyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-5-(p-tolyl(2,2,2-trifluoroethyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((5-(cyclopropylmethyl)(p-tolyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((5-(cyclopropylmethyl)(p-tolyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2-fluoro-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl) amino)isonicotinicacid

(S)-3-(((6-(2-fluoro-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl) amino)isonicotinicacid

(R)-3-(((6-(2,4-difluorophenyl)-2-methyl-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2,4-difluorophenyl)-2-methyl-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-chloro-2-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-chloro-2-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-isopropoxy-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-isopropoxy-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-isopropyl-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-isopropyl-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-chloro-3-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-chloro-3-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2-fluoro-6-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2-fluoro-6-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-isopropyl-2-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-isopropyl-2-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-cyclopropylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-cyclopropylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-isobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-isobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-cyclopropylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-cyclopropylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluoroethoxy)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluoroethoxy)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-isopropoxyphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-isopropoxyphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluroethyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluroethyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-((4-chlorophenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-((4-chlorophenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2-methyl-6-(2-(2,2,2-trifluroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2-methyl-6-(2-(2,2,2-trifluroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(2-cyclopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(2-cyclopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-dimethylamino)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-dimethylamino)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(methyl(4-(3,3,3-trifluoropropyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(methyl(4-(3,3,3-trifluoropropyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-(4-(2-cyclopropylethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-(4-(2-cyclopropylethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((6-((4-cyclobutylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((6-((4-cyclobutylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(6-methyl-2,3-dihydrobenzo-furan-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(6-methyl-2,3-dihydrobenzo-furan-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(5-methyl-2,3-dihydro-benzofuran-4-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(5-methyl-2,3-dihydro-benzofuran-4-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid

(R)-3-(((2-methyl-6-(phenylthio)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid

(S)-3-(((2-methyl-6-(phenylthio)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acidPreparation of the Substituted Pyridine Derivative Compounds

The compounds used in the reactions described herein are made accordingto organic synthesis techniques known to those skilled in this art,starting from commercially available chemicals and/or from compoundsdescribed in the chemical literature. Commercially available chemicalsare obtained from standard commercial sources including Acros Organics(Pittsburgh, Pa.), Aldrich Chemical (Milwaukee, Wis., including SigmaChemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), AvocadoResearch (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet(Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.), CrescentChemical Co. (Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman KodakCo. (Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), FisonsChemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICNBiomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall, U.K.),Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc.(Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co.(Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Spectrum QualityProduct, Inc. (New Brunswick, N.J.), TCI America (Portland, Oreg.),Trans World Chemicals, Inc. (Rockville, Md.), and Wako Chemicals USA,Inc. (Richmond, Va.).

Methods known to one of ordinary skill in the art are identified throughvarious reference books and databases. Numerous suitable reference booksand treatises that detail the synthesis of reactants useful in thepreparation of compounds described herein, or provide references toarticles that describe the preparation, are well known to those of skillin the art. See, e.g., SYNTH. ORG. CHEM. (John Wiley & Sons, Inc., NewYork); Sandler et al., ORG. FUNCT. GROUP PREP. (2nd Ed., Academic Press,New York, 1983); House, MOD. SYNTH. REACT. (2nd Ed., W. A. Benjamin,Inc., Menlo Park, Calif., 1972); Gilchrist, HETEROCYCL. CHEM. (2nd Ed.,John Wiley & Sons, New York, 1992); March, ADV. ORG. CHEM: REACT., MECH.& STR. (4th Ed., Wiley-Intersci., New York, 1992); Fuhrhop & Penzlin,ORG. SYNTH: CONCEPTS, METHS., STARTING MATER., 2ND, REVIS. & ENLARGEDED. (John Wiley & Sons,1994); Hoffman, ORG. CHEM., INTERMED. TEXT(Oxford Univ. Press, 1996); Larock, COMPR. ORG. TRANSFORM: GUIDE TOFUNCT. GROUP PREP. (2nd Ed., Wiley-VCH, 1999); MOD. CARBONYL CHEM.(Otera, ed., Wiley-VCH, 2000); Patai, PATAI'S 1992 GUIDE TO CHEM. FUNCT.GROUPS (Intersci., 1992); Solomons, ORG. CHEM. (7th Ed., John Wiley &Sons 2000); Stowell, INTERMED. ORG. CHEM. (2nd Ed. Wiley-Intersci.1993); INDUS. ORG. CHEM: STARTING MATER. & INTERMED: AN ULLMANN'SENCYCLO., in 8 vol. (John Wiley & Sons, 1999); ORG. REACT., in over 55vol. (John Wiley & Sons, 1942-2000); CHEM. FUNCT. GROUPS, in 73 vol.(John Wiley & Sons).

Specific and analogous reactants may also be identified through theindices of known chemicals, such as those prepared by the ChemicalAbstract Service of the American Chemical Society (Washington, D.C.),which are available in most public and university libraries, as well asthrough on-line databases. Chemicals that are known but not commerciallyavailable in catalogs can usually be prepared by custom chemicalsynthesis houses, and many of the standard chemical supply housesprovide custom synthesis services.

Substituted pyridine derivative compounds of the present embodiments canbe prepared by general synthetic routes, for example, as describedherein according to Schemes 1-3.

Referring to Scheme 1, above, compound A and an amine compound B aremixed and treated under a variety of conditions to form compound C. Forexample, the mixture of compound A and amine B can be subjected tomicrowave irradiation in an appropriate solvent, at temperatures rangingfrom 120° C. to 172° C. The ester compound E can be prepared fromcompound C and alcohol D using a coupling reagent, such as HATU, in thepresence of base.

Referring to Scheme 2, above, compound F and aldehyde compound G aremixed and treated under reductive amination conditions to form compoundC. The ester compound E can be prepared from compound C and alcohol Dusing a coupling reagent, such as HATU, in the presence of base.

Referring to Scheme 3, compound H and amine compound B are mixed andtreated under a variety of conditions to form compound E. For example,the mixture of compound H and amine B can be subjected to a Buchwaldreaction under microwave irradiation in an appropriate solvent, attemperatures ranging from 100° C. to 120° C. The ester compound E can behydrolyzed to give compound C, using basic conditions such as 1N aq.NaOH.

Pharmaceutical Compositions

In certain embodiments, a substituted pyridine derivative compound asdescribed herein may be administered as a pure chemical (i.e., compoundor salt thereof). In other embodiments, a substituted pyridinederivative compound described herein is combined with a pharmaceuticallysuitable or acceptable excipient or carrier (also referred to herein asa physiologically suitable or acceptable excipient or carrier) selectedon the basis of a chosen route of administration and standardpharmaceutical practice. See, e.g., REMINGTON: SCI. & PRACT. PHARM.(Gennaro, 21st Ed. Mack Pub. Co., Easton, Pa., 2005).

Accordingly, at least one embodiment provides a pharmaceuticalcomposition comprising at least one substituted pyridine derivativecompound or a stereoisomer, prodrug, pharmaceutically acceptable salt,hydrate, solvate, or N-oxide thereof, and at least one pharmaceuticallyacceptable excipient. One embodiment provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable excipient, and acompound of Formula 1, Formula 2, Formula 3, Formula 4, or a tautomer,stereoisomer, geometric isomer, N-oxide, or pharmaceutically acceptablesalt of these compounds. Another embodiment provides a pharmaceuticalcomposition comprising at least one substituted pyridine derivativecompound or a stereoisomer, prodrug, pharmaceutically acceptable salt,hydrate, solvate, or N-oxide thereof, and at least one pharmaceuticallyacceptable excipient, and further comprises at least one other activeagent, such as a therapeutic or prophylactic agent. Typically, anexcipient is acceptable or suitable if it is compatible with the othercomponents of the composition (e.g., active agents or excipients) andnot deleterious to the recipient (e.g., the subject or patient) of thecomposition.

In certain embodiments, the substituted pyridine derivative compound asdescribed by Formula 1, Formula 2, Formula 3, or Formula 4 issubstantially pure, in that it contains less than about 5%, or less thanabout 1%, or less than about 0.1%, of other organic small molecules,such as contaminating intermediates or by-products that are created, forexample, during compound synthesis.

Pharmaceutical compositions may be administered in a manner appropriateto the disease to be treated (or prevented) as determined by personsskilled in the medical arts. An appropriate dose and a suitable durationand frequency of administration will be determined by such factors asthe condition of the patient, the type and severity of the patient'sdisease, the particular form of the active ingredient, and the method ofadministration. In general, an appropriate dose and treatment regimenprovides the composition(s) in an amount sufficient to providetherapeutic and/or prophylactic benefit (e.g., an improved clinicaloutcome, such as more frequent complete or partial remissions, or longerdisease-free and/or overall survival, or a lessening of symptomseverity. Optimal doses may generally be determined using experimentalmodels and/or clinical trials. The optimal dose may depend upon the bodymass, weight, or blood volume of the patient.

The dose of a pharmaceutical composition comprising at least onesubstituted pyridine derivative compound as described herein may differ,depending upon the patient's (e.g., human) condition; that is, the stageof the disease, general health status, age, and other factors that aphysician or other person skilled in the medical art will use todetermine dose.

Accordingly, some embodiments provide an oral dosage form comprising thecompound of Formula 1, the compound of Formula 2, the compound ofFormula 3, or the compound of Formula 4. Suitable oral dosage formsinclude, for example, tablets, pills, sachets, or capsules of hard orsoft gelatin, methylcellulose or of another suitable materials easilydissolved in the digestive tract. Suitable nontoxic solid carriers canbe used which include, for example, pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharin, talcum,cellulose, glucose, sucrose, magnesium carbonate, and the like. See,e.g., Remington, 2005.

For the substituted pyridine derivative compounds described herein oraldoses typically range from about 1.0 mg to about 1000 mg, one to fourtimes, or more, per day.

A related embodiment provides a pharmaceutical formulation, for examplea diluted version of the pharmaceutical composition or the compound ofFormula 1, the compound of Formula 2, the compound of Formula 3 or thecompound of Formula 4; wherein the diluent is suitable for intravenousinfusion of the diluted pharmaceutical composition or the compound ofFormula 1, the compound of Formula 2, the compound of Formula 3, or thecompound of Formula 4. An example pharmaceutical formulation comprisesthe pharmaceutical composition or compound of Formula 2 and saline ordextrose as a diluent.

Histone Demethylases

In each mammalian cell, about 2 meters of linear DNA is packaged tightlyenough to fit inside the roughly 10 μm diameter cell nucleus, yet stillensure appropriate access for required gene expression. The basicpackage unit, a nucleosome, comprises a segment of DNA wound in sequencearound eight histone protein cores. These nucleosomes, in turn, arefolded through a series of successively higher ordered chromatinstructures that form the chromosome. Because histones are the majorprotein component of chromatin, histone modification, for example, bymethylation, acetylation, demethylation, or deacetylation, has profoundeffects on chromatin structure. Several classes of enzymes are knownthat modify histones at various sites.

More specifically, histones can be modified (post-translation) byacetylation, methylation, phosphorylation, or ubiquitination.Methylation is catalyzed by histone methyltransferases that transfermethyl groups from S-adenyosyl methionine to histones. Specificmethylation targets include amino groups in lysine residues and theguanidino groups of arginines, by carboxymethylation of aspartate,glutamate, or of the C-terminus of the protein. Histone methylation isknown to participate in a diverse range of biological processesincluding heterochromatin formation, X-chromosome inactivation, andtranscriptional regulation. Histone methylation, then, is acharacterized modification of the “histone code,” that along with DNAmethylation provides an epigenetic code. See Lachner et al., 116 J. CellSci. 2117 (2003); Margueron et al., 15 Curr. Opin. Genet. Devel. 163(2005).

Methylated lysines are perhaps the best understood marks of the histonecode, yet this code remains complex because each of the four standardhistones can be simultaneously modified at multiple different sites withmultiple different modifications. There are four histone families, and,for example histone H3 contains nineteen lysines known to beindependently methylated: each can be un-, mono-, di- or tri-methylated.The patterns of histone lysine methylation have been standardized andrefer to the histone family, K (standard abbreviation of lysine), theposition residue methylated, and the number of methyl groups added(e.g., “me3” means three methyl groups); accordingly H3K4me3 meanstrimethylation of lysine 4 on histone H3. Unlike acetylation, whichgenerally correlates with transcriptional activation, whether histonemethylation leads to transcription activation or repression depends onthe particular site of methylation and the degree of methylation (e.g.,whether a particular histone lysine residue is mono-, di-, ortri-methylated). In general, methylation of histone H3K9, H3K27, andH4K20 is associated with transcriptional repression; conversely,demethylation of H3K4 is correlated with silencing of the genomicregion. Methylation of lysines H3K4, H3K36, and H3K79 is generallyassociated with transctiptional activation; and tri- and di-methylationof H3K4 (H3K4me3 and H3K4me2, respectively) generally marks thetranscriptional start sites of actively transcribed genes, whereasmono-methylation of H3K4 (H3K4me) is associated with enhancer sequences.

A “demethylase” or “protein demethylase,” in the context of the presentembodiments, is an enzyme that removes at least one methyl group from anamino acid side chain of histones, e.g., act as a histone H3 or H4demethylase. For example, a H3 demethylase may demethylate one or moreof H3K4, H3K9, H3K27, H3K36, or H3K79. Alternately, a H4 demethylase maydemethylate H4K20. Demethylases can demethylate mono-, di- or atri-methylated substrate, and can act on a methylated core histonesubstrate, a mononucleosome substrate, a dinucleosome substrate, or annucleosome substrate, peptide substrate, or chromatin (e.g., in acell-based assay). Aptly named, lysine specific demethylase 1(LSD1/KDM1) was the first lysine-specific histone demethylasediscovered, and this enzyme demethylates both mono- and di-methylatedH3K4 and H3K9, using flavin as a cofactor.

A second class of histone demethylases containing a Jumonji C (JmjC)domain was confirmed using a formaldehyde release assay and H3K36; thisclass was named “JmjC domain containing histone demethylase 1”(JHDM1/KDM2A). Additional JmjC domain-containing proteins wereidentified subsequently, and they can be phylogenetically clustered intoseven subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8,UTX/UTY, and JmjC domain only.

JMJD2 Family

The JMJD2 jumonji proteins are histone-demethylases that demethylatetri- and di-methylated H3K9, and were the first identified histonetri-methyl demethylase. In particular, ectopic expression of JMJD2family members dramatically decreases levels of H3K9me3 and H3K9me2, andincreases levels of H3K9me; which delocalizes Heterochromatin Protein 1(HP1) and reduces overall levels of heterochromatin in vivo. Members ofthe JMJD2 subfamily of jumonji proteins include JMJD2C and itshomologues JMJD2A, JMJD2B, JMJD2D, and JMJD2E. Common structuralfeatures found in the JMJD2 subfamily of Jumonji proteins include theJmjN, JmjC, PHD and Tdr sequences.

JMJD2C, also known as GASC1 and KDM4C, is known to demethylate H3K9me3and H3K36me3. Histone demethylation by JMJD2C occurs via a hydroxylationreaction dependent on iron and α-ketoglutarate, wherein oxidativedecarboxylation of α-ketoglutarate by JMJD2C produces carbon dioxide,succinate, and ferryl and ferryl subsequently hydroxylates methylatedlysine H3K9, releasing formaldehyde. JMJD2C is known to modulateregulation of adipogenesis by the nuclear receptor PPARγ and is known tobe involved in regulation of self-renewal in embryonic stem cells.

JARID Family

JARID proteins in the JARID1 subfamily include JARID1A, JARID1B,JARID1C, and JARID1D proteins, and the JARID2 subfamily, as well ashomologues thereof. Further descriptions and listings of JARID proteinscan be found elsewhere. See Klose et al., 7 Nat. Rev. Genet. 715 (2006).The JARID1 family proteins contain several conserved domains: JmjN,ARID, JmjC, PHD, and a C5HC2 zing finger.

JARID1A, also called KDM5A or RBP2, was found initially as a bindingpartner of retinoblastoma (Rb) protein. JARID1A was subsequently foundto function as a demethylase of H3K4me3 and H3K4me2, and has been foundto promote cell growth, while inhibiting senescence and differentiation.For instance, abrogation of JARID1A from mouse cells inhibits cellgrowth, induces senescence and differentiation, and causes loss ofpluripotency of embryonic stem cells in vitro. JARID1A has been found tobe overexpressed in gastric cancer and the loss of JARID1A has beenfound to reduce tumorigenesis in a mouse cancer model. Additionally,studies have demonstrated that loss of the retinoblastome bindingprotein 2 (RBP2) histone demethylase suppresses tumorigenesis in micelacking Rb1 or Men1, indicating that RBP2-inhibitory drugs might haveanti-cancer activity. Lin et al., 108 PNAS 13379 (2011).

JARID1B, also referred to as KDM5B and PLU1, was found originally inexperiments regarding genes regulated by the HER2 tyrosine kinase.Consistently, research has shown that JARID1B is expressed in breastcancer cell lines, while restriction of JARID1B has been found in normaladult tissues with the exception of the testis. JARID1B is alsoapparently up-regulated in prostate cancers, but has more limitedexpression in benign prostate; and is also up-regulated in bladdercancer and lung cancer (both SCLC and NSCLC). In addition, 90% ofinvasive ductal carcinomas express JARID1B. Finally, JARID1B has beenfound to repress tumor suppressor genes such as BRCA1, CAV1, and14-3-3a; and knockdown of JARID1B increases the levels of tri-methylatedH3K4 at these genes.

UTX/UTY Family

UTX/UTY family includes KDM6A, KDM6B, and UTY. KDM6A (also called UTX)and KDM6B (also called JMJD3), act on H3K27me2 and H3K27me3 and areimportant for development, whereas the substrate and role of UTY remainsto be elucidated. Both KDM6A (UTX) and KDM6B (JMJD3) have demonstratedtumor-supressive characteristics by functioning as antagonists againstthe oncogenic polycomb group (PcG) proteins. PcG proteins are importantrepressive histone marks that catalyze the tri- and di-methylation ofH3K27. PcG genes have been characterized as oncogenes that arefrequently overexpressed or amplified in cancer.

Accordingly, at least one embodiment provides a method for inhibiting ahistone-demethylase enzyme comprising contacting the enzyme with asubstituted pyridine derivative compound as disclosed herein. In aspecific embodiment, the histone-demethylase enzyme comprises a JmjCdomain. Another embodiment provides a method for inhibiting ahistone-demethylase enzyme comprising contacting the enzyme with asubstituted pyridine derivative compound as disclosed herein, whereinthe histone-demethylase enzyme is JARID1A, JARID1B, JMJD2C, or JMJD3. Inone embodiment, a method for inhibiting the histone-demethylase enzymeJMJD3 comprises contacting the JMJD3 enzyme with a substituted pyridinederivative compound as disclosed herein. In another embodiment, a methodfor inhibiting the histone-demethylase enzyme JMJD2C comprisescontacting the JMJD2C enzyme with a substituted pyridine derivativecompound as disclosed herein.

Methods of Treatment

Disclosed herein are methods of modulating demethylation in a cell or ina subject, either generally or with respect to one or more specifictarget genes. Demethylation can be modulated to control a variety ofcellular functions, including without limitation: differentiation;proliferation; apoptosis; tumorigenesis, leukemogenesis or otheroncogenic transformation events; hair loss; or sexual differentiation.For example, particular embodiments herein provide a method of treatinga disease regulated by histone methylation or demethylation in a subjectin need thereof by modulating the activity of at least one demethylasecomprising a JmjC domain. In a specific embodiment, the histonedemethylase is a JHDM protein.

Another aspect of the present embodiments provides methods of treatingcancer or neoplastic disease comprising administering at least onecompound described herein to a patient in need thereof. In a furtheraspect of a method for treating cancer in a patient, the cancer isprostate cancer, breast cancer, bladder cancer, lung cancer, ormelanoma. In particular embodiments, the neoplastic disease is multipleendocrine neoplasia type 1. In a particular embodiment, the cancer isretinoblastoma. An embodiment provides a method of treating cancer in apatient in need thereof comprising administering to the patient acompound of Formula 1, or a pharmaceutical composition comprising acompound of Formula 1. Another embodiment provides a method of treatingcancer in a patient in need thereof comprising administering to thepatient a compound of Formula 2, or a pharmaceutical compositioncomprising a compound of Formula 2. Another embodiment provides a methodof treating cancer in a patient in need thereof comprising administeringto the patient a compound of Formula 3, or a pharmaceutical compositioncomprising a compound of Formula 3. Another embodiment provides a methodof treating cancer in a patient in need thereof comprising administeringto the patient a compound of Formula 4, or a pharmaceutical compositioncomprising a compound of Formula 4.

In an additional aspect of the present embodiments provides a method ofinhibiting the growth of a tumor or tumor or neoplastic cells comprisingexposing (e.g., contacting) the tumor or cells with at least onecompound described herein. In a particular embodiment, the tumor ischaracterized by a loss of retinoblastoma gene (RB1) function. In aparticular embodiment, the tumor is characterized by a loss of multipleendocrine neoplasia type 1 gene (Men1) function. In an embodiment, amethod for inhibiting the growth of a tumor or tumor cells comprisesexposing the tumor to a compound of Formula 1, a composition comprisinga compound of Formula 1, or pharmaceutically composition comprising acompound of Formula 1. In an embodiment, a method for inhibiting thegrowth of a tumor or tumor cells comprises exposing the tumor to acompound of Formula 2, a composition comprising a compound of Formula 2,or pharmaceutically composition comprising a compound of Formula 2. Inan embodiment, a method for inhibiting the growth of a tumor or tumorcells comprises exposing the tumor to a compound of Formula 3, acomposition comprising a compound of Formula 3, or pharmaceuticallycomposition comprising a compound of Formula 3. In an embodiment, amethod for inhibiting the growth of a tumor or tumor cells comprisesexposing the tumor to a compound of Formula 4, a composition comprisinga compound of Formula 4, or pharmaceutically composition comprising acompound of Formula 4.

Another aspect of the present embodiments provides use of at least onecompound described herein as a medicament or for making a medicament fortreating cancer or neoplastic disease. The cancer or neoplastic diseasefor which the medicament is manufactured may be prostate cancer, breastcancer, bladder cancer, lung cancer, melanoma, retinoblastoma, ormultiple endocrine neoplasia type 1. At least one embodiment provides ause a compound of Formula 1 or composition comprising a compound ofFormula 1. Another embodiment provides a use a compound of Formula 2 orcomposition comprising a compound of Formula 2. Another embodimentprovides a use a compound of Formula 3 or composition comprising acompound of Formula 3. Yet another embodiment provides a use a compoundof Formula 4 or composition comprising a compound of Formula 4.

Other embodiments and uses will be apparent to one skilled in the art,in light of this Specification. The following examples are providedmerely as illustrative of various embodiments and shall not be construedto limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants, J are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Preparation of common intermediate6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester was performed according to the following outline:

Step A:2-(6-Bromo-3,4-dihydro-isoquinolin-1-ylmethyl)-isoindole-1,3-dione

To a solution of (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid (1 g,4.87 mmol) in CH₃CN (25 mL) was added 2-(3-bromo-phenyl)-ethylamine(1.08 g, 5.36 mmol) and POCl₃ (3.0 g, 19.8 mmol). The reaction mixturewas refluxed overnight. The solution was concentrated in vacuo, and theresidue was neutralized with aqueous NaHCO₃. The aqueous phase wasextracted with DCM, and the organic layers were dried with Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography (EA:PE=1:1) to obtain title compound (0.6 g, 35%).

Step B:2-(6-Bromo-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-isoindole-1,3-dione

To a mixture of2-(6-bromo-3,4-dihydro-isoquinolin-1-ylmethyl)-isoindole-1,3-dione (400mg, 1.08 mmol) in AcOH (10 mL) was added NaBH₄ (85 mg, 2.16 mmol)portionwise at 0° C. (9.5 g, 61.4 mmol). The reaction mixture wasstirred at ambient temperature (“temp”) overnight. The reaction mixturewas neutralized with aq. NaHCO₃ and extracted with DCM. The organiclayers were dried with Na₂SO₄ and concentrated in vacuo to afford thetitle crude compound (400 mg, 100%), which was used directly in the nextstep without further purification.

Step C:6-Bromo-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of2-(6-bromo-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)isoindole-1,3-dione(8.0 g, 21.6 mmol) in DCM (50 mL) was added (Boc)₂O (5.7 g, 25.9 mmol)and DIEA (5.9 g, 43.2 mmol). The reaction mixture was stirred at ambienttemp for 2 hr. Aqueous NH₄Cl was added, and the organic layers werecollected and concentrated in vacuo. The residue was purified by flashcolumn chromatography (EA:PE=1:1) to afford the title compound (4.5 g,45%).

Step D: 1-Aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of6-bromo-1-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.5 g, 9.6 mmol) in CH₃CN (50 mL) was addedH₂NNH₂.H₂O (2.7 g, 96 mmol), and the reaction mixture was refluxedovernight. Upon reaction completion, the mixture was concentrated invacuo. The resulting residue was taken up in DCM, and the organic layerswere successively washed with water and brine, dried with Na₂SO₄, andconcentrated in vacuo. The residue was purified by purified by flashcolumn chromatography (DCM:MeOH=1:1) to afford the title compound (2.5g, 76%).

Step E:6-Bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of1-aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (2.5 g, 7.35 mmol) in toluene under N₂ atmosphere wasadded 3-bromoisonicotinic acid methyl ester (1.98 g, 8.82 mmol),Pd₂(dba)₃ (340 mg, 0.37 mmol), Xant-phos (260 mg, 0.45 mmol) and Cs₂CO₃(3.36 g, 10.3 mmol). The reaction mixture refluxed overnight. Uponcompletion, the reaction mixture was filtered, and the filtrate wasconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (EA:PE=1:4) to afford the title compound (1.8 g,51.4%).

Step R:(R)-6-Bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, and(S)-6-Bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of1-aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (2.5 g, 7.35 mmol) in toluene under N₂ was added3-bromo-isonicotinic acid methyl ester (1.98 g, 8.82 mmol), Pd₂(dba)₃(340 mg, 0.37 mmol), Xant-phos (260 mg, 0.45 mmol) and Cs₂CO₃ (3.36 g,10.3 mmol). The reaction mixture was refluxed overnight. Uponcompletion, the reaction mixture was filtered, and the filtrate wasconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (EA:PE=1:4) to afford the title compound (1.8 g,51.4%). NMR (400 MHz, CDCl₃): δ 1.34-1.49 (d, 9H), 2.74-2.31 (m, 2H),3.21-3.37 (m, 1H), 3.52-3.66 (m, 2H), 3.89 (s, 3H), 3.96-4.28 (m, 1H),5.31-5.47 (m, 1H), 7.06 (d, J=10.8 Hz, 1H), 7.34-7.37 (m, 2H), 7.61-7.67(m, 2H), 7.93-7.97 (m, 1H), 8.34-8.64 (m, 1H). [M+H] Calc'd forC₂₂H₂₆BrN₃O₄: 476; Found: 476. Optionally the racemic compound wassubjected to chiral separation: Column, Superchiral S-OD, 0.46 cmI.D.*25 cm L; mobile phase: CO₂/IPA/DE, A=75/25/0.05; flow rate (“F”):2.5 mL/min; wave length (“W”): UV 245 nm; temperature (“T”): 35° C.;retention time (“RT”): 4.014 min, 4.241 min.

Step S: tert-butyl(R)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-6-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate,and tert-butyl(S)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-6-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Suzuki coupling of the enantiomers were carried out as follows: To asolution of(R)-6-bromo-1-[(4-methoxycarbonylpyridin-3-ylamino)methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester or(S)-6-Bromo-1-[(4-methoxycarbonylpyridin-3-ylamino)methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (350 mg, 0.74 mmol) in toluene (30 mL) under N₂atmosphere was added 2-methylphenylboronic acid (150 mg, 1.1 mmol),Pd(PPh₃)₄ (43 mg, 0.04 mmol), and Cs₂CO₃ (720 mg, 2.2 mmol). Thereaction mixture refluxed overnight. Upon completion, the reactionmixture was taken up in EA, and the combined organic layers weresuccessively washed with water, brine, dried with Na₂SO₄, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (EA:PE=1:3) to afford the title compound (350 mg,83%). [M+H] Calc'd for C₂₉H₃₃N₃O₄, 488; Found, 488.

Example 1A and Example 1B3-[({(1S)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid; and3-[({(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid Step F:1-[(4-Methoxycarbonyl-pyridin-3-ylamino)-methyl]-6-(methyl-p-tolyl-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (110 mg, 0.23 mmol) in toluene (30 mL) under N₂atmosphere was added N-methyl-p-tolyl-amine (34 mg, 0.28 mmol),Pd₂(dba)₃ (11 mg, 0.012 mmol), Xant-phos (20 mg, 0.035 mmol) and Cs₂CO₃(105 mg, 0.32 mmol). The reaction mixture was allowed to refluxovernight. Upon completion, the reaction mixture was taken up in EA, andthe combined organic layers were successively washed with water andbrine, dried with Na₂SO₄, and concentrated in vacuo. The resultingresidue was purified by flash column chromatography (EA:PE=1:4) toafford (90 mg, 75%) the title compound. Chiral separation usingprep-HPLC (Chiralpak IA 5 um 4.6*250 mm, Phase: Hex:IPA=70:30, F: 1.0mL/min; W: 230 nm; T: 30° C.) afforded two optically active compounds:

3-[({(1S)-6-[methyl(4-tolyl)amino]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid; and3-[({(1R)-6-[methyl(4-tolyl)amino]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid

Hydrolysis and de-protection of Boc of each of the enantiomers werecarried out as follows: To a solution of1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-6-(methyl-p-tolyl-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (80 mg, 0.155 mmol) in THF/H₂O (1:1, 10 mL) wasadded LiOH.H₂O (16 mg, 0.62 mmol). The mixture was stirred overnight atambient temp. Upon completion, the reaction mixture was concentrated invacuo and the residue was adjusted to pH 3 with HCl (2N). The aqueouslayers were extracted with EA (thrice) and the combined organic layerswere dried with Na₂SO₄ and concentrated in vacuo. The residue wasdissolved in DCM (10 mL) followed by TFA (1 mL). The reaction mixturewas stirred for 2 hr and concentrated in vacuo, affording the titlecompound (65% to 80% yields). The analytical data for the twoenantiomers are identical. ¹H NMR (400 MHz, Methanol-d₄): δ 2.32 (s,3H), 3.00-3.07 (m, 2H), 3.29 (s, 3H), 3.33-3.39 (m, 1H), 3.57-3.64 (m,1H), 3.85-3.93 (m, 1H), 4.04-4.10 (m, 1H), 4.78-4.81 (m, 1H), 6.68-6.75(m, 2H), 7.02 (d, J=10.8 Hz, 2H), 7.16-7.22 (m, 3H), 8.02 (d, J=7.6 Hz,1H), 8.12 (d, J=7.6 Hz, 1H), 8.43 (s, 1H). [M+H] Calc'd for C₂₄H₂₆N₄O₂:403; Found: 403.

Example 2A and Example 2B3-[({(1S)-6-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid; and3-[({(1R)-6-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid Step G:1-[(4-Methoxycarbonyl-pyridin-3-ylamino)-methyl]-6-[2-methyl-4-(2,2,2-trifluoro-ethoxy)-phenyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (400 mg, 0.84 mmol) in toluene (30 mL) under N₂atmoshpere was added 2,2,2-trifluoro-1-[3-methyl-4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenoxy]ethane (400 mg, 1.26 mmol), Pd(PPh₃)₄(50 mg, 0.043 mmol), and Cs₂CO₃ (825 mg, 2.53 mmol). The reactionmixture was refluxed overnight. Upon completion, the reaction mixturewas taken up in EA, and the combined organic layers successively washedwith water and brine, dried with Na₂SO₄, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography(EA:PE=1:4) to afford the title compound (380 mg, 78%). Chiralseparation using prep-HPLC (Chiralpak IA 5 um 4.6*250 mm, Phase:Hex:EtOH=80:20, F: 1.0 mL/min, W: 230 nm, T: 30° C.) afforded twooptically active compounds:

The title compounds were prepared in 85 to 88% yield according to theprocedure of Example 1A. ¹H NMR (400 MHz, Methanol-d₄): δ 2.23 (s, 3H),3.17-3.23 (m, 2H), 3.29-3.31 (m, 1H), 3.43-3.52 (m, 1H), 3.67-3.73 (m,1H), 4.14-4.20 (m, 1H), 4.50-4.59 (m, 2H), 4.98-5.02 (m, 1H), 6.87-6.95(m, 2H), 7.14 (d, J=10.8 Hz, 1H), 7.25-7.28 (m, 2H), 7.51 (d, J=10.8 Hz,1H), 7.97-8.00 (m, 2H), 8.44 (s, 1H). [M+H] Calc'd for C₂₅H₂₄F₃N₃O₃:472; Found: 472.

Example 3A and Example 3B3-{[((1S)-6-{methyl[4-(methylethyl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolyl)methyl]amino}pyridine-4-carboxylicacid; and3-{[((1R)-6-{methyl[4-(methylethyl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolyl)methyl]amino}pyridine-4-carboxylicacid

The title compounds were prepared in 80% yield according to theprocedure of Example 1A. ¹H NMR (400 MHz, Methanol-d₄): δ 1.25 (d, J=7.2Hz, 6H), 2.87-3.06 (m, 3H), 3.29 (s, 3H), 3.34-3.40 (m, 1H), 3.59-3.65(m, 1H), 3.81-3.87 (m, 1H), 4.02-4.07 (m, 1H), 4.79-4.85 (m, 1H), 6.70(d, J=2.4 Hz, 1H), 6.76-6.79 (m, 1H), 7.06 (d, J=8.4 Hz, 2H), 7.21-7.25(m, 3H), 7.90 (d, J=4.8 Hz, 1H), 7.97 (d, J=3.2 Hz, 1H), 8.34 (s, 1H).[M+H] Calc'd for C₂₆H₃₀N₄O₂: 431; Found: 431.

Example 4A and Example 4B3-[({(1S)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid; and3-[({(1R)-6-[4-(cyclopropyl-methoxy)-2-methylphenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid

The title compounds were prepared in 72 to 75% yield according to theprocedure of Example 1A. NMR (400 MHz, Methanol-d₄): δ 0.34-0.38 (m,2H), 0.59-0.65 (m, 2H), 1.23-1.29 (m, 1H), 2.20 (s, 3H), 3.16-3.30 (m,2H), 3.42-3.50 (m, 1H), 3.67-3.72 (m, 1H), 3.81 (d, J=4.8 Hz, 2H),3.90-3.98 (m, 1H), 4.12-4.18 (m, 1H), 4.92-5.00 (m, 1H), 6.76-6.82 (m,2H), 7.07 (d, J=10.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.49 (d, J=10.4 Hz,1H), 7.90 (d, J=6.8 Hz, 1H), 7.99 (J=7.2 Hz, 1H), 8.41 (s, 1H). [M+H]Calc'd for C₂₇H₂₉N₃O₃, 444; Found, 444.

Preparation of common intermediate methyl3-[({(1S)-2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylateand methyl 3-[({(1R)-2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylate wasachieved according to the following outline:

Step A: 5-Bromo-1-oxo-1,3-dihydro-isoindole-2-carboxylic acid tert-butylester

To a solution of 5-bromo-2,3-dihydro-isoindol-1-one (10.0 g, 47.4 mmol)in THF (100 mL) was added a solution of (Boc)₂O (20.6 g, 94.5 mmol), andDMAP (0.57 g, 4.6 mmol). The reaction mixture was stirred at ambienttemp overnight. Upon completion, the reaction mixture was concentratedin vacuo, and the residue was purified by flash column chromatography(EA:PE=1:10) to afford the title compound (13 g, 88%).

Step B: 5-Bromo-1-hydroxy-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

To a solution of 5-bromo-1-oxo-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester (5.0 g, 16.0 mmol) in anhydrous THF (10 mL) at −78° C.under argon was added a 1.5 M solution of diisobutylaluminum hydride inhexane (16 mL, 24.0 mmol) dropwise. The reaction mixture was stirred at−78° C. for 2 hr. The reaction was quenched with saturated aqueoussodium acetate (50 mL) and allowed to warm to room temp. A 3:1 mixtureof diethyl ether and saturated aqueous ammonium chloride (320 mL) wasadded and the resulting mixture was stirred at room temp until asuspension formed. The solid was filtered under reduced pressure andwashed with diethyl ether (twice, 50 mL). The organic layers werecollected, and the aqueous layer was extracted with diethyl ether(thrice, 100 mL). The combined organic layers were successively washedwith water (50 mL) and brine (50 mL), dried over sodium sulfate,filtered, and concentrated in vacuo. The crude solid were used in thenext step without further purification.

Step C: 5-Bromo-1-methoxy-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

To a solution of the5-bromo-1-hydroxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butylester in MeOH (50 mL) was added pyridinium p-toluensulfonate (500 mg,1.9 mmol). The reaction mixture was stirred at room temp for 2 hr andthen quenched with triethylamine (2.4 g, 23.7 mmol). The reaction wasconcentrated in vacuo to give the title compound, which was used in thenext step without further purification.

Step D: 5-Bromo-1-cyano-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester

To a solution of crude5-bromo-1-methoxy-1,3-dihydro-isoindole-2-carboxylic acid tert-butylester in anhydrous CH₂Cl₂ (50 mL) was added trimethylsilyl cyanide(TMSCN, 3.0 mL, 24.1 mmol), and boron trifluoride-diethyl etherate (3.0mL, 24.1 mmol) at −78° C. under argon. The reaction mixture was stirredat −78° C. for 1 hr, and then quenched with saturated NaHCO₃ (50 mL).The resulting mixture was allowed to warm to room temp and stirred for 2hr. The biphasic solution was partitioned and the aqueous phase wasextracted with CH₂Cl₂ (3×40 mL). The combined organic layers were driedover magnesium sulfate, filtered, and concentrated in vacuo. Theresulting residue was purified by flash chromatography (EA:PE=1:30) toafford the title compound as a white solid (3 g, 58%). ¹H NMR (300 MHz,CDCl₃): δ 1.57 (s, 9H), 4.72 (s, 2H), 5.70 (s, 1H), 7.29-7.37 (m, 1H),7.50-7.54 (m, 2H).

Step E: 1-Aminomethyl-5-bromo-1,3-dihydroisoindole-2-carboxylic acidtert-butyl ester

To a solution of the 5-bromo-1-cyano-1,3-dihydroisoindole-2-carboxylicacid tert-butyl ester (1.2 g, 3.7 mmol) in EtOH (20 mL) was added RaneyNi (100 mg in 2 mL water). The reaction mixture was stirred overnightunder H₂ at ambient temp. The reaction mixture was filtered throughCelite, and the filtrate was concentrated in vacuo to provide the titlecompound (1.2 g, 100%).

Step F:5-Bromo-1-[(2-methoxycarbonyl-phenylamino)-methyl]-1,3-dihydro-isoindole-2-carboxylicacid tert-butyl ester

To a solution of1-aminomethyl-5-bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butylester (1.2 g, 3.68 mmol) in toluene under N₂ atmosphere was added3-bromoisonicotinic acid methyl ester (0.87 g, 4.02 mmol), Pd₂(dba)₃(169 mg, 0.18 mmol), Xant-phos (319 mg, 0.55 mmol), and Cs₂CO₃ (1.68 g,5.15 mmol). The reaction mixture was stirred at reflux overnight. Uponcompletion, the reaction was concentrated in vacuo, and residue waspurified by flash chromatography (EA:PE=1:2) to afford the titlecompound (0.4 g, 19%).

Step G: methyl3-[({(1S)-2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylateand methyl3-[({(1R)-2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylate

Chiral separation using prep-SFC (Superchiral S-OZ 5 ul 4.6*250 mm,CO₂:IPA:DEA=60:40:0.05, F: 2.5 mL/min, W: 254 nm, T: 35° C.) affordedtwo optically active compounds (2.46 min and 3.13 min).

Example 5A and Example 5B3-[({(1S)-5-[methyl(4-methylphenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylicacid; and3-[({(1R)-5-[methyl(4-methylphenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylicacid

To a solution of methyl3-[({2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylate(50 mg, 0.11 mmol) in toluene (10 mL) under N₂ atmosphere was addedN-methyl-p-tolyl-amine (26 mg, 0.21 mmol), Pd₂(dba)₃ (5 mg, 0.005 mmol),Xant-phos (9 mg, 0.015 mmol), and Cs₂CO₃ (49 mg, 0.15 mmol). Thereaction mixture was refluxed overnight. Upon completion, the reactionmixture was taken up in EA and successively washed with water and brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby flash chromatography (EA:PE=1:2) to afford methyl3-[({2-[(tert-butyl)oxycarbonyl]-5-[methyl(4-methylphenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylate(50 mg, 92%) as oil.

To the solution of methyl 3-[({2-[(tert-butyl)oxycarbonyl]-5-[methyl(4-methyl-phenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylate(50 mg, 0.099 mmol) in THF/H₂O (1:1,10 mL) was added LiOH.H₂O (16 mg,0.62 mmol). The mixture was stirred at ambient temp overnight. Thereaction was concentrated in vacuo and the pH adjusted to ˜pH 3 with HCl(2N). The aqueous layers were extracted with EA (thrice), and thecombined organic layers were dried with Na₂SO₄ and concentrated invacuo. The residue was dissolved in DCM (10 mL) followed by dropwiseaddition of TFA (1 mL) and allowed to stir at ambient temp for 2 hr.Upon completion, the reaction mixture was concentrated in vacuo toafford the title compounds (68 to 84%). The analytical data for the twoenantiomers are identical. ¹H NMR (400 MHz, Methanol-d₄): δ 2.33 (s,3H), 3.25 (s, 3H), 3.84-3.91 (m, 1H), 4.02-4.08 (m, 1H), 4.46-4.62 (m,2H), 5.19-5.22 (m, 1H), 6.78-6.81 (m, 2H), 7.01 (d, J=8.4 Hz, 2H), 7.18(d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 1H), 7.97-8.07 (m, 2H), 8.38 (s,1H). [M+H] Calc'd for C₂₃H₂₄N₄O₂: 403; Found: 403.

Example 6A and Example 6B3-{[((1S)-5-{methyl[4-(methylethyl)phenyl]amino}isoindolinyl)methyl]amino}pyridine-4-carboxylicacid; and3-{[((1R)-5-{methyl[4-(methylethyl)phenyl]amino}isoindolinyl)methyl]amino}pyridine-4-carboxylicacid

The title compounds were prepared in 44 to 58% yield according to theprocedure of Example 5A. ¹H NMR (300 MHz, Methanol-d₄): δ 1.25 (d, J=6.6Hz, 6H), 2.88-2.92 (m, 1H), 3.26 (s, 3H), 3.85-3.88 (m, 1H), 4.00-4.02(m, 1H), 4.45-4.57 (m, 2H), 5.17-5.20 (m, 1H), 6.80-6.83 (m, 2H), 7.05(d, J=8.4 Hz, 2H), 7.22-7.30 (m, 3H), 7.93-7.95 (m, 2H), 8.33 (s, 1H).[M+H] Calc'd for C₂₅H₂₈N₄O₂, 416; Found, 416.

Example 7A and 7B3-[({(1S)-5-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]isoindolinyl}methyl)amino]pyridine-4-carboxylicacid; and 3-[({(1R)-5-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]iso-indolinyl}methyl)amino]pyridine-4-carboxylic acid

To a solution of methyl3-[({2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylate(50 mg, 0.11 mmol) in toluene (10 mL) under N₂ atmosphere was added2,2,2-trifluoro-1-[3-methyl-4-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))phenoxy]ethane(68 mg, 0.21 mmol), Pd(PPh₃)₄, (12 mg, 0.01 mmol), and Cs₂CO₃ (106 mg,0.32 mmol). The reaction mixture refluxed overnight. Upon completion,the reaction mixture was taken up in EA and successively washed withwater and brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography (EA:PE=1:2) to affordmethyl3-[({(2-[(tert-butyl)oxycarbonyl]-5-[2-methyl-4-(2,2,2-trifluoroethoxy)-phenyl]isoindolinyl}methyl)amino]pyridine-4-carboxylate(80%) as oil.

To the solution of methyl3-[({2-[(tert-butyl)oxycarbonyl]-5-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]isoindolinyl}methyl)-amino]pyridine-4-carboxylate(50 mg, 0.087 mmol) in THF/H₂O (1:1, 10 mL) was added LiOH.H₂O (16 mg,0.62 mmol). The mixture was stirred overnight at ambient temp. Thereaction was concentrated in vacuo, and the pH adjusted to ˜pH 3 withHCl (2N). The aqueous layers were extracted thrice with EA, and thecombined organic layers were dried with Na₂SO₄ and concentrated invacuo. The residue was dissolved in DCM (10 mL) followed by dropwiseaddition of TFA (1 mL) and the reaction mixture stirrd at ambient tempfor 2 hr. Upon completion, the reaction mixture was concentrated invacuo to afford the title compound (66 to 76%). ¹H NMR (400 MHz,Methanol-d₄): δ 2.20 (s, 3H), 4.00-4.02 (m, 1H), 4.13-4.15 (m, 1H),4.50-4.56 (m, 2H), 4.64-4.74 (m, 2H), 5.37-5.40 (m, 1H), 6.88-6.95 (m,2H), 7.13 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H), 7.58 (d, J=9.9 Hz, 1H),7.97-8.04 (m, 2H), 8.43 (s, 1H). [M+H] Calc'd for C₂₄H₂₂F₃N₃O₃: 457;Found: 457.

Example 8A and Example 8B(R)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Hydrolysis and de-protection of Boc of each of the enantiomers werecarried out as follows: To a solution of tert-butyl(R)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-6-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylateor(S)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-6-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(90 mg, 0.18 mmol) in THF/H₂O (1:1, 10 mL) was added LiOH.H₂O (24 mg,0.55 mmol). The mixture was stirred overnight at ambient temp. Uponcompletion, the reaction mixture was concentrated in vacuo and theresidue was adjusted to pH ˜3 with HCl (2N). The aqueous layers wereextracted with EA (3×5 mL) and the combined organic layers were driedwith Na₂SO₄ and concentrated in vacuo. The residue was dissolved in DCM(10 mL) followed by TFA (1 mL). The reaction mixture was stirred for 2hr and concentrated in vacuo affording the title compound (70 mg, 75%).NMR (400 MHz, Methanol-d₄): δ 2.23 (s, 3H), 3.18-3.24 (m, 2H), 3.47-3.60(m, 1H), 3.69-3.74 (m, 1H), 3.97-4.03 (m, 1H), 4.16-4.20 (m, 1H),5.01-5.03 (m, 1H), 7.15-7.30 (m, 6H), 7.53 (d, J=10.8 Hz, 1H), 8.04-8.07(m, 2H), 8.49 (s, 1H). [M+H] Calc'd for C₂₃H₂₃N₃O₂: 374; Found: 374.

Example 9A and Example 9B(R)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds were prepared up to 80% yield according tothe procedure of Example 8A and 8B. NMR (400 MHz, Methanol-d₄): δ 1.05(t, J=7.6 Hz, 3H), 2.57 (q, J=7.6 Hz, 2H), 3.15-3.23 (m, 2H), 3.45-3.52(m, 1H), 3.69-3.75 (m, 1H), 3.99-4.05 (m, 1H), 4.18-4.23 (m, 1H),5.03-5.06 (m, 1H), 7.11-7.32 (m, 6H), 7.52 (d, J=8.4 Hz, 1H), 8.06 (d,J=5.2 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.54 (s, 1H). [M+H] Calc'd forC₂₄H₂₅N₃O₂: 388; Found: 388.

Step T: tert-butyl(R)-6-((4-ethylphenyl)(methyl)amino)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;and tert-butyl(S)-6-((4-ethylphenyl)(methyl)amino)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Buchwald reactions of the enantiomers were carried out as follows: To asolution of(R)-6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (80 mg, 0.17 mmol) in toluene (30 mL) under N₂atmosphere was added 4-ethyl-N-methylaniline (27 mg, 0.20 mmol),Pd₂(dba)₃ (8 mg, 0.01 mmol), Xant-phos (6 mg, 0.01 mmol) and Cs₂CO₃ (80mg, 0.24 mmol). The reaction mixture was refluxed overnight. Uponcompletion, the reaction mixture was taken up in EA and the combinedorganic layers were successively washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo. The resulting residue was purified byflash column chromatography (EA:PE=1:3) to afford (40 mg, 44%) the titlecompound. [M+H] Calc'd for C₃₁H₃₈N₄O₄: 531; Found: 531.

Example 10A and Example 10B(R)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 50% yield according tothe procedure of Example 8A and 8B. NMR (400 MHz, Methanol-d₄): δ 1.24(t, J=7.2 Hz, 3H), 2.65 (q, J=7.2 Hz, 2H), 2.96-3.12 (m, 2H), 3.29 (s,3H), 3.34-3.41 (m, 1H), 3.59-3.65 (m, 1H), 3.85-3.91 (m, 1H), 4.05-4.09(m, 1H), 4.82-4.93 (m, 1H), 6.69-6.77 (m, 2H), 7.04 (d, J=8.4 Hz, 2H),7.20-7.22 (m, 3H), 8.01-8.10 (m, 2H), 8.42-8.50 (m, 1H). [M+H] Calc'dfor C₂₅H₂₈N₄O₂: 417; Found: 417.

Step U:(R)-2-(6-Bromo-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-isoindole-1,3-dione,and(S)-2-(6-Bromo-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-isoindole-1,3-dione

To a solution of2-(6-bromo-3,4-dihydro-isoquinolin-1-yl-methyl)-isoindole-1,3-dione(111.1g, 301 mmol) in DMF (500 mL) was added RuCl(p-cymene) [(R,R)-Ts-DPEN] orRuCl(p-cymene) [(S,S)-Ts-DPEN] (19.2 g, 30.1 mmol) at room temp. Amixture of HCO₂H (100 mL) and TEA (40 mL) was added dropwise at 0° C.The mixture was stirred at ambient temp for 4 hr. Upon completion, thesolution was diluted with H₂O, and the pH was adjusted with Na₂CO₃ to˜pH 10. The solution was extracted thrice with DCM (800 mL). The organiclayers were successively washed with H₂O, brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography (EA:PE=1:4 to 1:1) to afford the title compound (82.0 g,73.4%) as a white solid. [M+H] Calc'd for C₁₈H₁₅BrN₂O₂: 371; Found: 371.

Step V:(R)-6-bromo-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,4-dihydro-1H-iso-quinoline-2-carboxylicacid tert-butyl ester, and(S)-6-Bromo-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

To a solution of2-(6-bromo-1,2,3,4-tetrahydro-isoquinolin-1-ylmethyl)-isoindole-1,3-dione(82.0 g, 221 mmol) in DCM (800 mL) was added (Boc)₂O (57.8 g, 265 mmol)and DIEA (57.0 g, 442 mmol). The reaction mixture was stirred at ambienttemp for 6 hr. Aqueous NH₄Cl was added, and the organic layer wasconcentrated in vacuo. The residue was purified by flash columnchromatography (EA:PE=1:10 to 1:5) to afford the title compound (93 g,93.6%) as a white solid. [M+H] Calc'd for C₂₃H₂₃BrN₂O₄: 471; Found: 471.

Step W:(R)-1-Aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester, and(S)-1-Aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester

To a solution of(R)-6-bromo-1-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester or(S)-6-bromo-1-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (55 g, 117 mmol) in CH₃CN (500 mL) was addedH₂NNH₂.H₂O (117 g, 2.34 mol); the reaction mixture was refluxed for 6hr. Upon reaction completion, the mixture was concentrated in vacuo. Theresulting residue was dissolved in DCM, and successively washed withwater, brine, dried over Na₂SO₄, and concentrated in vacuo to afford thetitle compound (39.7 g, 100%) as pink oil. [M+H] Calc'd forC₁₅H₂₁BrN₂O₂: 341; Found, 341.

Step X:(R)-6-Bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester; and(S)-6-Bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

A mixture of(R)-1-aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester or(S)-1-aminomethyl-6-bromo-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester (39.7 g, 117 mmol), 3-bromo-isonicotinic acid methylester (30.3 g, 140 mmol), Pd₂(dba)₃ (5.38 g, 5.84 mmol), Xant-phos (4.05g, 7.01 mmol) and Cs₂CO₃ (53.3 g, 163 mmol) in toluene (300 mL) wasstirred overnight at 120° C. under N₂ atmosphere. Upon completion, thereaction mixture was filtered, and the filtrate was concentrated invacuo. The resulting residue was purified by flash column chromatography(EA:PE=1:20 to 1:4) to afford the title compound (28.0 g, 50.1%) as ayellow solid. [M+H] Calc'd for C₂₂H₂₆BrN₃O₄: 476; Found: 476.

Step Y:(R)-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-6-(methyl-p-tolyl-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester, and(S)-1-[(4-methoxy-carbonyl-pyridin-3-ylamino)-methyl]-6-(methyl-p-tolyl-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

A mixture of(R)-6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester or(S)-6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.0 g, 8.40 mmol), N-methyl-p-tolyl-amine (1.22g, 10.1 mmol), Pd2(dba)3 (387 mg, 0.42 mmol), Xant-phos (729 mg, 1.26mmol) and Cs2CO3 (3.83 g, 11.8 mmol) in toluene (80 mL) stirredovernight at 120° C. under N₂ atmosphere. Upon completion, the reactionmixture was filtered, and the filtrate was concentrated in vacuo. Theresulting residue was purified by flash column chromatography(EA:PE=1:10 to 1:5) to afford the title compound (3.16 g, 72.8%) asyellow oil. [M+H] Calc'd for C₃₀H₃₆N₄O₄: 517; Found: 517.

Step Z: Methyl(R)-3-(((6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinate, and methyl(S)-3-(((6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinate

To a solution of(R)-1-[(4-methoxycarbonyl-pyridin-3-ylamino)-methyl]-6-(methyl-p-tolyl-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester or(S)-1-[(4-methoxy-carbonyl-pyridin-3-ylamino)-methyl]-6-(methyl-p-tolyl-amino)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (3.16 g, 6.11 mmol) in DCM (30 mL) was added TFA(10 mL) at ambient temp and stirred for 2 hr. Upon completion, theresulting solution was concentrated in vacuo. The residue wasneutralized with saturated NaHCO₃ and extracted thrice with EA (100 mL).The organic layers were successively washed with brine, dried overNa₂SO₄ and concentrated in vacuo to afford the title compound (2.54 g,99.6%) as yellow oil. [M+H] Calc'd for C₂₅H₂₈N₄O₂: 417; Found: 417.

Step A1: Methyl(R)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinate,and methyl(S)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinate

To a solution of(R)-3-{[6-(methyl-p-tolyl-amino)-1,2,3,4-tetrahydroisoquinolin-1-yl-methyl]amino}isonicotinicacid methyl ester or(S)-3-{[6-(methyl-p-tolyl-amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl-methyl]amino}isonicotinicacid methyl ester (2.54 g, 6.11 mmol) and DIEA (1.58 g, 12.2 mmol) inDMSO was added a solution of CH₃I (865 mg, 6.11 mmol) in DMSO (50 mL)dropwise. The mixture was stirred at ambient temp for 2 hr. Uponcompletion, the solution was diluted with H₂O and extracted with DCM(100 mL). The organic layers were successively washed with H₂O (thricewith 80 mL), brine, dried over Na₂SO₄, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography(MeOH:DCM=1:40) to afford the title compound (1.4 g, 53.2%) as yellowoil. [M+H] Calc'd for C₂₆H₃₀N₄O₂: 431; Found: 431.

Example 11A and Example 11B(R)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

A mixture of(R)-3-{[2-methyl-6-(methyl-p-tolyl-amino)-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl]amino}isonicotinicacid methyl ester or(S)-3-{[2-methyl-6-(methyl-p-tolyl-amino)-1,2,3,4-tetrahydroisoquinolin-1-ylmethyl]amino}isonicotinicacid methyl ester (1.4 g, 3.25 mmol) and LiOH.H₂O (410 mg, 9.74 mmol) inTHF/H₂O (20 mL) was stirred overnight at room temp. Upon completion, thevolume of the reaction mixture was reduced in vacuo and the pH adjustedwith HCl (1N) to ˜pH 7. The precipitate was filtered and the filter cakedried in vacuo to afford the title compound (1.05 g, 77.8%) as a yellowsolid. [M+FH] Calc'd for C₂₅H₂₈N₄O₂: 417; Found: 417.

NMR (400 MHz, CD₃OD): δ 8.07 (s, 1H), 7.82 (d, J=4.8 Hz, 1H), 7.69 (d,J=4.8 Hz, 1H), 7.15-7.12 (m, 3H), 7.00-6.97 (m, 2H), 6.74 (d, J=8.4 Hz,1H), 6.65 (s, 1H), 4.41 (t, J=5.6 Hz, 1H), 3.76 (d, J=6.0 Hz, 2H),3.67-3.63 (m, 1H), 3.24-3.18 (m, 4H), 3.01-2.98 (m, 2H), 2.87 (s, 3H),2.31 (s, 3H).

Step B1. tert-butyl(R)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-6-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate;and tert-butyl(S)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-6-(o-tolyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

Suzuki coupling of the enantiomers were carried out as follows: Amixture of(R)-6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester or(S)-6-bromo-1-[(4-methoxycarbonyl-pyridin-3-ylamino)methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (900 mg, 1.89 mmol), 2-methyl-phenylboronic acid(311 mg, 2.29 mmol), Pd(PPh₃)₄ (108 mg, 0.095 mmol) and Cs₂CO₃ (1.85 g,5.67 mmol) in toluene (40 mL) stirred overnight at 120° C. under N₂atmosphere. Upon completion, the reaction mixture was filtered, and thefiltrate concentrated in vacuo. The resulting residue was purified byflash column chromatography (EA:PE=1:10 to 1:5) to afford the titlecompound (921 mg, 99.8%) as yellow oil. [M+H] Calc'd for C₂₉H₃₃N₃O₄:488; Found: 488.

Example 12A and Example 12B(R)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared according to the procedure forExample 8A and Example 8B. NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.77(d, J=5.2 Hz, 1H), 7.49 (d, J=4.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H),7.27-7.19 (m, 3H), 7.16-7.10 (m, 1H), 7.08 (d, J=1.6 Hz, 1H), 7.05 (s,1H), 3.82-3.81 (m, 1H), 3.71-3.61 (m, 2H), 3.16-3.11 (m, 1H), 2.88-2.82(m, 2H), 2.70-2.65 (m, 1H), 2.50 (s, 3H), 2.19 (s, 3H). [M+H] Calc'd forC₂₄H₂₅N₃O₂: 388; Found: 388.

Example 13A and Example 13B(R)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared in 86% yield according to theprocedure for Example 11A and Example 11B. NMR (400 MHz, CD₃OD): δ 8.06(s, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.69 (d, J=4.8 Hz, 1H), 7.17-7.12 (m,3H), 7.01-6.99 (m, 2H), 6.75 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 4.42-4.39(m, 1H), 3.77 (d, J=5.2 Hz, 2H), 3.66-3.62 (m, 1H), 3.26-3.18 (m, 4H),3.00-2.98 (m, 2H), 2.86 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 1.22 (t, J=7.6Hz, 3H). [M+H] Calc'd for C₂₆H₃₀N₄O₂: 431; Found: 431.

Example 14A and Example 14B(R)-3-(((2-methyl-6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((2-methyl-6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared according to the procedure forExample 11A and Example 11B. NMR (400 MHz, CD₃OD) δ 8.10 (s, 1H), 7.86(d, J=5.2 Hz, 1H),7.70 (d, J=4.8 Hz, 1H), 7.17-7.14 (m, 3H), 7.02 (d,J=8.0 Hz, 2H), 6.78-6.75 (m, 1H), 6.68 (d, J=2.0 Hz, 1H), 4.57-4.54 (m,1H), 3.82-3.81 (m, 2H), 3.76-3.73 (m, 1H), 3.33-3.30 (m, 1H), 3.25 (s,3H), 3.06-3.03 (m, 2H), 2.94 (s, 3H), 2.59-2.55 (m, 2H), 1.67-1.61 (m,2H), 0.97-0.93 (m, 2H). [M+H] Calc'd for C₂₇H₃₂N₄O₂: 445; Found: 445.

Example 15A and Example 15B(R)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 66% yield according tothe procedure for Example 12A and Example 12B. NMR (400 MHz, CD₃OD): δ8.22 (s, 1H), 7.75 (d, J=4.8 Hz, 1H), 7.49 (d, J=4.8 Hz, 1H), 7.36-7.26(m, 3H), 7.23-7.18 (m, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.05 (d, J=8.0 Hz,1H), 7.01 (s, 1H), 3.80 (t, J=4.0 Hz, 1H), 3.66-3.61 (m, 2H), 3.16-3.10(m, 1H), 2.88-2.81 (m, 2H), 2.69-2.64 (m, 1H), 2.53-2.48 (m, 2H), 2.48(s, 3H), 1.01 (t, J=7.6 Hz, 3H). LCMS: [M+H] Calc'd for C₂₅H₂₇N₃O₂: 402;Found: 402.

Example 16A and Example 16B(R)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds were prepared up to 42% yield according tothe procedure for Example 12A and Example 12B. NMR (400 MHz, DMSO-d6): δ8.25 (s, 1H), 7.75 (d, J=5.2 Hz, 1H), 7.48 (d, J=4.8 Hz, 1H), 7.40-7.29(m, 3H), 7.18 (m, 1H), 7.08 (d, J=6.4 Hz, 1H), 7.01 (m, 2H), 3.80 (t,J=4.0 Hz, 1H), 3.67-3.65 (m, 2H), 3.14-3.11 (m, 1H), 2.94-2.81 (m, 3H),2.67-2.66 (m, 1H), 2.51 (s, 3H), 1.08 (m, 6H). LCMS: [M+H] Calc'd forC₂₆H₂₉N₃O₂: 416; Found: 416.

Example 17A and Example 17B(R)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared according to the procedure forExample 12A and Example 12B. NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H),7.74 (d, J=4.8 Hz, 1H),7.45 (d, J=5.2 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H),7.15-7.05 (m, 3H), 6.86-6.84 (m, 2H), 3.81 (s, 1H), 3.70-3.66 (m, 2H),3.12-3.09 (m, 1H), 2.86-2.78 (m, 2H), 2.67-2.65 (m, 1H), 2.50 (s, 3H),1.96 (s, 3H), 1.84 (s, 3H). [M+H] Calc'd for C₂₅H₂₇N₃O₂: 402; Found:402.

Step C1: tert-butyl(R)-5-bromo-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)iso-indoline-2-carboxylate;and tert-butyl(S)-5-bromo-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)isoindoline-2-carboxylate

Chiral separation using prep-SFC (Superchiral S-OZ 5 μl 4.6*250 mm,CO₂:IPA:DEA=60:40:0.05, F: 2.5 mL/min, W: 254 nm, T: 35° C.) affordedtwo optically active compounds (2.46 min and 3.13 min). NMR (CDCl3, 400MHz): δ 8.44 (s, 1H), 7.95-7.88 (m, 1H), 7.62-7.55 (m, 1H), 747-7.36 (m,3H), 7.20-7.10 (m, 1H), 5.29-5.19 (m, 1H), 4.85-4.48 (m, 2H), 3.92-3.90(m, 4H), 3.80-3.77 (m, 1H), 1.54 (s, 9H). LCMS: [M+H] Calc'd forC₂₁H₂₄BrN₃O₄: 462; Found: 462.

Step D1:3-[({(1S)-5-[methyl(4-methylphenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylicacid, and3-[({(1R)-5-[methyl(4-methylphenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylicacid

To a solution of methyl3-[({2-[(tert-butyl)oxycarbonyl]-5-bromoisoindolinyl}methyl)amino]pyridine-4-carboxylate(4.5 g, 9.72 mmol) in toluene (100 mL) under N₂ atmosphere was addedN-methyl-p-tolyl-amine (1.4 g, 11.66 mmol), Pd₂(dba)₃ (450 mg, 0.5mmol), Xant-phos (840 mg, 1.5 mmol), and Cs₂CO₃ (4.5 g, 13.6 mmol). Thereaction mixture was refluxed overnight. Upon completion, the reactionmixture was taken up in EA and successively washed with water and brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby flash chromato-graphy (EA:PE=1:4) to afford methyl3-[({2-[(tert-butyl)oxycarbonyl]-5-[methyl (4-methylphenyl)amino]isoindolinyl}methyl)amino]pyridine-4-carboxylate (2.6 g,54%) as oil. LCMS: [M+H] Calc'd for C₂₉H₃₄N₄O₄: 503; Found: 503.

Example 18A and Example 18B(R)-3-(((2-methyl-5-(methyl(p-tolyl)amino)isoindolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((2-methyl-5-(methyl(p-tolyl)amino)isoindolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 65% yield according tothe procedure for Example 11A and 11B. NMR (400 MHz, CD3OD): δ 8.49 (s,1H), 8.30 (d, J=6.0 Hz, 1H), 8.06 (d, J=6.0 Hz, 1H), 7.27-7.19 (m, 3H),7.04 (d, J=8.4 Hz, 2H), 6.83-6.79 (m, 2H), 5.10-5.09 (m, 1H), 4.94-4.89(m, 1H), 4.45-4.42 (m, 1H), 4.17-4.00 (m, 2H), 3.27 (s, 3H), 3.14 (s,3H), 2.33 (s, 3H). LCMS: [M+H] Calc'd for C₂₄H₂₆N₄O₂: 403; Found: 403.

Example 19A and Example 19B(R)-3-(((5-((4-ethylphenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((5-((4-ethylphenyl)(methyl)amino)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 87% yield according tothe procedure for Example 18A and 18B. NMR (400 MHz, CD3OD): δ 8.35 (s,1H), 8.01-7.97 (m, 2H), 7.28-7.21 (m, 3H), 7.06 (d, J=8.4 Hz, 2H),6.85-6.78 (m, 2H), 5.07-5.05 (m, 1H), 4.90-4.85 (m, 1H), 4.47-4.41 (m,1H), 4.14-4.09 (m, 1H), 3.98-3.95 (m, 1H), 3.27 (s, 3H), 3.14 (s, 3H),2.64 (q, J=7.2 Hz, 1H), 1.24 (t, J=7.2 Hz, 3H). LCMS: [M+H] Calc'd forC₂₅H₂₈N₄O₂: 417; Found: 417.

Example 20A and Example 20B(R)-3-(((2-methyl-5-(methyl(4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinicacid, and(S)-3-(((2-methyl-5-(methyl(4-propyl-phenyl)amino)iso-indolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 60% yield according tothe procedure for Example 18A and 18B. NMR (400 MHz, CD3OD): δ 8.34 (s,1H), 8.02-7.97 (m, 2H), 7.27-7.19 (m, 3H), 7.06-7.03 (m, 2H), 6.84-6.78(m, 2H), 5.07-5.04 (m, 1H), 4.90-4.85 (m, 1H), 4.44-4.40 (m, 1H),4.13-4.09 (m, 1H), 3.98-3.93 (m, 1H), 3.27 (s, 3H), 3.13 (s, 3H), 2.58(t, J=7.2 Hz, 2H), 1.69-1.59 (m, 2H), 0.95 (t, J=7.2 Hz, 3H). LCMS:[M+H] Calc'd for C₂₆H₃₀N₄O₂: 431; Found: 431.

Step E1: tert-butyl(R)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-5-(o-tolyl)isoindoline-2-carboxylate;and tert-butyl(S)-1-(((4-(methoxycarbonyl)pyridin-3-yl)amino)methyl)-5-(o-tolyl)isoindoline-2-carboxylate

A mixture of tert-butyl(1R)-5-bromo-1-({[4-(methoxycarbonyl)(3-pyridyl)]amino}methyl)isoindoline-2-carboxylate(200 mg, 0.43 mmol), 2-methylphenylboronic Acid (118 mg, 0.86 mmol),Pd(PPh₃)₄ (25 mg, 0.02 mmol) and Cs₂CO₃ (420 mg, 1.29 mmol) in toluene(40 mL) stirred overnight at 120° C. under N₂. Upon completion, thereaction mixture was filtered, and the filtrate concentrated in vacuo.The resulting residue was purified by flash column chromatography(EA:PE=1:3) to afford the title compound (130 mg, 65%) as yellow oil.[M+H] Calc'd for C₂₈H₃₁N₃O₄: 474; Found: 474.

Example 21A and Example 21B(R)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinicacid; and(S)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 60% yield according tothe procedure for Example 12A and 12B. NMR (400 MHz, CD3OD): δ 8.19 (s,1H), 8.80 (d, J=5.2 Hz, 1H), 7.71 (d, J=4.8 Hz, 1H), 7.55 (d, J=7.6 Hz,1H), 7.30-7.12 (m, 6H), 5.07-5.04 (m, 1H), 4.90-4.85 (m, 1H), 4.28-4.25(m, 1H), 4.11-4.07 (m, 1H), 3.96-3.92 (m, 1H), 3.01 (s, 3H), 2.18 (s,3H). LCMS: [M+H] Calc'd for C₂₃H₂₃N₃O₂: 374; Found: 374.

Example 22A and Example 22B(R)-3-(((5-(2-ethylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinicacid; and(S)-3-(((5-(2-ethylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinicacid

Each of the title compounds was prepared up to 47% yield according tothe procedure for Example 21A and 21B. NMR (400 MHz, CD₃OD): δ 8.25 (s,1H), 7.86 (d, J=5.2 Hz, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.57 (d, J=7.6 Hz,1H), 7.34-7.29 (m, 4H), 7.23-7.20 (m, 1H), 7.11 (d, J=7.6 Hz, 1H),5.10-5.03 (m, 2H), 4.44 (d, J=14.4 Hz, 1H), 4.18-4.14 (m, 1H), 4.04-3.99(m, 1H), 3.11 (s, 3H), 2.53 (q, J=7.6 Hz, 2H), 1.03 (t, J=7.6 Hz, 3H).LCMS: [M+H] Calc'd for C₂₄H₂₅N₃O₂: 388; Found: 388.

Additional embodiments of a compound of Formula 2 are shown in Table 3(“Example” refers to a Chemical Synthesis Example prepared according tothe “Example preparation” example as described above):

TABLE 3 Example prepara- Example Compound IUPAC name tion H¹ NMR and MS23A and 3-({[(8 1R)-6-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquino- 2A andNMR (400 MHz, CD₃OD+ DMSO-d6): 23Blin-1-yl]methyl}amino)pyridine-4-carboxylic acid; and 2B δ 3.14-3.23(2H, m), 3.37-3.42 (1H, m),3-({[(1S)-6-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquino- 3.61-3.66 (1H,m), 3.91-3.97 (1H, m), lin-1-yl]methyl}amino)pyridine-4-carboxylic acid4.13-4.18 (1H, m), 4.91-4.94 (1H, m), 7.52-7.69 (5H, m), 7.83 (1H, t, J= 1.6

Hz), 7.92 (1H, d, J = 5.2 Hz), 8.03 (1H, d, J = 5.2 Hz), 8.97 (1H s).[M + H] Calc'd for C₂₀H₁₉N₃O₂S: 366; Found: 366.

24A and 3-({[(1R)-6-[2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]- 2A andNMR (400 MHz, CD₃OD): δ 3.14-3.25 24B1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}amino) 2B (2H,m), 3.42-3.49(1H, m), 3.66-3.73 pyridine-4-carboxylic acid; and3-({[(1S)-6-[2-fluoro-4- (1H, m), 3.93-4.00 (1H, m), 4.14-4.19(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydro- (1H, m), 4.57-4.65(2H, m), 4.99-5.01 isoquinolin-1-yl]methyl}amino)pyridine-4- (1H, m),6.92-6.97 (2H, m), 7.43-7.56 carboxylic acid (4H, m), 8.02 (2H, s), 8.49(1H, s). [M + H] Calc'd for C₂₄H₂₁F₄N₃O₃, 476; Found, 476.

25A and 3-({[(1R)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydroiso- 2A andNMR (400 MHz, CD₃OD): δ 3.20-3.29 25Bquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid; 2B (2H, m),3.46-3.49 (1H, m), 3.68-3.73 and3-({[(1S)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydro- (1H, m), 3.92-3.96(lH,m), 4.13-4.17 isoquinolin-1-yl]methyl}amino)pyridine-4- (1H, m),4.96-5.01 (1H, m), 7.05-7.09 carboxylic acid (2H, m), 7.48-7.57 (4H, m),7.93 (1H, d, J = 5.2 Hz), 7.99 (1H, d, J = 5.2 Hz),

8.42 (1H, s). [M + H] Calc'd for C₂₂H₁₉F₂N₃O₂: 396; Found: 396.

26A and (R)-3-(((6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetra- 2A and NMR(400 MHz, CD₃OD): δ 3.20-3.28 26Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; 2B (2H, m),3.45-3.51 (1H, m), 3.69-3.73 and(S)-3-(((6-(4-chloro-2-fluorophenyl)-1,2,3,4- (1H, m), 3.95-4.02 (1H,m), 4.16-4.20 tetrahydroisoquinolin-1-yl)methyl)amino) (1H, m),5.02-5.04 (1H, m), 7.30-7.34 isonicotinic acid (2H, m), 7.48-7.58 (4H,m), 8.05 (1H, d, J = 4.8 Hz), 8.12 (1H, d, J = 4.8 Hz),

8.51 (1H, s). [M + H] Calc'd for C₂₂H₁₉ClFN₃O₂: 412; Found: 412.

27A and (R)-3-(((6-(4-isopropoxy-2-methylphenyl)-1,2,3,4- 8A and NMR(400 MHz, CD₃OD): δ 1.32 (6H, 27Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 8B d, J = 8.0 Hz)2.21 (3H, s), 3.16-3.21 acid; and(S)-3-(((6-(4-isopropoxy-2-methylphenyl)- (2H, m), 3.44-3.49 (1H, m),3.67-3.73 1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) (1H, m),3.90-4.00 (lH, m), 4.15-4.20 isonicotinic acid (1H, m), 4.60-4.64 (1H,m), 5.02-5.04 (1H, m), 6.76-6.81 (2H, m), 6.90 (1H, d,

J = 11.2 Hz), 7.24-7.28 (2H, m), 7.49 (1H, d, J = 10.4 Hz), 8.02 (2H,s), 8.47 (1H, s). [M + H] Calc'd for C₂₆H₂₉N₃O₃: 432; Found: 432.

28A and (R)-3-(((6-(4-isopropyl-2-methylphenyl)-1,2,3,4-tetra- 8A andNMR (400 MHz, CD₃OD): δ 1.27 (6H, 28Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; 8B d, J = 9.2 Hz)2.22 (3H, s), 2.85-2.95 and(S)-3-(((6-(4-isopropyl-2-methylphenyl)-1,2,3,4- (1H, m), 3.16-3.27 (2H,m), 3.43-3.52 tetra-hydroisoquinolin-1-yl)methyl)amino) (1H, m),3.67-3.71 (1H, m), 3.95-4.00 isonicotinic acid (1H, m), 4.15-4.22 (1H,m), 4.95-5.04 (1H, m), 7.07-7.14 (3H, m), 7.25-7.29

(2H, m), 7.51 (1H, d, J = 10.8 Hz), 8.03- 8.05 (2H, m), 8.48 (1H, s).[M + H] Calc'd for C₂₆H₂₉N₃O₂: 416; Found: 416.

29A and (R)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)- 8A and NMR (400MHz, CD₃OD): δ 2.21 (3H, 29B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)iso- 8B s), 3.16-3.26(2H, m), 3.44-3.52 (1H, m), nicotinic acid; and(S)-3-(((6-(4-(difluoromethoxy)-2- 3.67-3.73 (1H, m), 3.90-4.00 (1H, m),methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) 4.14-4.20 (1H, m),4.93-5.03 (1H, m), methyl)amino)isonicotinic acid 6.85 (1H, t, J = 13.6Hz), 7.01-7.09 (2H, m), 7.19-7.29 (3H, m), 7.55 (1H, d, J =

10.8 Hz), 8.01-8.08 (2H, m), 8.50 (1H, s). [M + H] Calc'd forC₂₄H₂₃F₂N₃O₃: 440; Found: 440.

30A and (R)-3-(((6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetra- 8A and NMR(400 MHz, CD₃OD): δ 1.06 (3H, 30Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; 8B t, J = 10.4 Hz)1.74-1.86 (2H,m), 2.21 and(S)-3-(((6-(2-methyl-4-propoxyphenyl)-1,2,3,4- (3H, s), 3.16-3.25 (2H,m), 3.44-3.49 tetrahydro-isoquinolin-1-yl)methyl)amino) (1H, m),3.67-3.73 (1H, m), 3.88-4.00 isonicotinic acid (3H, m), 4.15-4.20 (1H,m), 4.88-5.01 (1H, m), 6.77-6.81 (2H, m), 7.08 (1H, d,

J = 11.2 Hz), 7.24-7.28 (2H, m), 7.47- 7.51 (1H, m), 8.00 (2H, s), 8.48(1H, s). [M + H] Calc'd for C₂₆H₂₉N₃O₃: 432; Found: 432.

31A and (R)-3-(((6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydro- 8A andNMR (400 MHz, CD₃OD): δ 3.20-3.27 31Bisoquinolin-1-yl)methyl)amino)isonicotinic acid; and 8B (2H, m),3.45-3.49 (1H, m), 3.67-3.73(S)-3-(((6-(4-chloro-3-fluorophenyl)-1,2,3,4- (1H, m), 3.90-3.96 (1H,m), 4.12-4.19 tetrahydroiso-quinolin-1- (1H, m), 4.98-5.02 (1H, m),7.46-7.64 yl)methyl)amino)isonicotinic acid (6H, m), 7.95-8.01 (2H, m),8.43 (1H, s). [M + H] Calc'd for C₂₂H₁₉ClFN₃O₂;

412; Found, 412.

32A and (R)-3-(((6-(2-fluoro-6-methoxyphenyl)-1,2,3,4- 8A and NMR (400MHz, CD₃OD): δ 3.17-3.22 32Btetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic 8B (2H, m),3.45-3.49 (1H, m), 3.69-3.76 acid; and(S)-3-(((6-(2-fluoro-6-methoxyphenyl)-1,2,3,4- (4H, m), 3.95-4.03 (1H,m), 4.16-4.22 tetrahydroiso-quinolin-1-yl)methyl)amino) (1H, m),4.99-5.04 (1H, m), 6.80 (1H, t, isonicotinic acid J = 12.0 Hz), 6.91(1H, d, J = 11.2 Hz), 7.29-7.35 (3H, m), 7.51 (1H, d, J = 10.8

Hz), 8.06 (1H, d, J = 7.6 Hz), 8.17 (1H, d, J = 7.6 Hz), 8.53 (1H, s).[M + H] Calc'd: 408; Found: 408.

33A and (R)-3-(((6-(4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)- 8A and NMR(400 MHz, CD₃OD): δ 1.96-2.04 33B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)iso- 8B (2H, m),2.78-2.82 (2H, m), 3.07-3.18 nicotinic acid; and(S)-3-(((6-(4-(3,4-dihydroquinolin- (2H, m), 3.39-3.48 (1H, m),3.61-3.73 1(2H)-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) (3H, m),4.01-4.08 (1H, m), 4.17-4.23 methyl)amino)isonicotinic acid (1H, m),4.96-5.01 (1H, m), 6.73-6.80 (2H, m), 6.90-6.95 (1H, m), 7.05-7.18

(3H, m), 7.39-7.42 (1H, m), 8.12 (1H, d, J = 7.6 Hz), 8.35-8.39 (1H, m),8.68 (1H, s). [M + H] Calc'd for C₂₅H₂₆N₄O₂: 415; Found: 415.

34A and (R)-3-(((6-(4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)- 8A andNMR (400 MHz, CD₃OD): δ 3.35-3.42 34B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino 8B (3H, m), 3.48-3.52(1H, m), 3.71-3.77 isonicotinic acid; and (S)-3-(((6-(4-(3,4-dihydro-(1H, m), 4.03-4.14 (4H, m), 4.23-4.28isoquinolin-2(1H)-yl)phenyl)-1,2,3,4-tetrahydro- (1H, m), 4.82-4.86 (2H,m), 5.12-5.13 isoquinolin-1-yl)methyl)amino)isonicotinic acid (1H, m),7.25-7.34 (4H, m), 7.67-7.81 (3H, m), 8.14 (1H, d, J = 7.6 Hz), 8.38

(1H, d, J = 7.6 Hz), 8.77 (1H, s). [M + H] Calc'd for C₂₅H₂₆N₄O₂: 415;Found: 415.

35A and (R)-3-(((6-(4-isopropyl-2-methoxyphenyl)-1,2,3,4-tetra- 8A andNMR (400 MHz, CD₃OD): δ 1.19 (6H, 35Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; 8B d, J = 6.8 Hz),2.83-2.86 (1H, m), 3.08- and(S)-3-(((6-(4-isopropyl-2-methoxyphenyl)-1,2,3,4- 3.32 (2H, m),3.35-3.37 (1H, m), 3.58- tetra-hydroisoquinolin-1-yl)methyl)amino) 3.61(1H, m), 3.69 (3H, s), 3.86-3.89 isonicotinic acid (1H, m), 4.04-4.07(1H, m), 4.87-4.89 (1H, m), 6.80-6.84 (2H, m), 7.09 (1H, d,

J = 7.6 Hz), 7.31-7.36 (3H, m), 7.95-7.97 (2H, m), 8.47 (1H, s). [M + H]Calc'd for C₂₆H₂₉N₃O₃: 432; Found: 432.

36A and (R)-3-(((6-(4-(indolin-1-yl)phenyl)-1,2,3,4-tetrahydroiso- 8Aand NMR (400 MHz, CD₃OD): δ 2.25 (3H, 36Bquinolin-1-yl)methyl)amino)isonicotinic acid; and (S)-3- 8B s),3.06-3.18 (4H, m), 3.40-3.46 (1H, m),(((6-(4-(indolin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin- 3.64-3.70(1H, m), 3.88-3.94 (3H, m), 1-yl)methyl)amino)isonicotinic acid4.00-4.14 (1H, m), 4.83-4.90 (1H, m), 6.87 (1H, d, J = 8.0 Hz),7.01-7.08 (3H,

m), 7.18-7.20 (1H, m), 7.37-7.42 (1H, m), 8.03 (1H, d, J = 5.2 Hz), 8.13(1H, d, J = 5.2 Hz), 8.46 (1H, s). [M + H] Calc'd for C₂₅H₂₆N₄O₂: 415;Found: 415.

37A and (R)-3-(((6-((4-cyclopropylphenyl)(methyl)amino)- 10A and NMR(400 MHz, CD₃OD): δ 0.64-0.68 37B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) 10B (2H, m), 0.93-0.98(2H, m), 1.88-1.92 isonicotinic acid; and(S)-3-(((6-((4-cyclopropylphenyl) (1H, m), 3.00-3.07 (2H, m), 3.25 (3H,s), (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) 3.34-3.39 (1H,m), 3.60-3.63 (1H, m), methyl)amino)isonicotinic acid 3.86-3.91 (1H, m),4.05-4.09 (1H, m), 4.82-4.84 (1H, m), 6.68-6.75 (2H, m),

7.02 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.21 (1H, d, J = 9.2Hz), 8.02 (1H, d, J = 5.2 Hz), 8.09 (1H, d, J = 5.2 Hz), 8.42 (1H, s).[M + H] Calc'd for C₂₆H₂₈N₄O₂: 429; Found: 429.

38A and (R)-3-(((6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetra- 10A andNMR (400 MHz, CD₃OD): δ 0.97 (3H, 38Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; 10B t, J = 9.6Hz), 1.52-1.70 (2H, m), 2.57- and(S)-3-(((6-(methyl(4-propylphenyl)amino)-1,2,3,4- 2.62 (2H, m),3.02-3.09 (2H, m), 3.25 tetra-hydroisoquinolin-1-yl)methyl)amino) (3H,s), 3.34-3.42 (1H, m), 3.60-3.66 isonicotinic acid (1H, m), 3.86-3.94(1H, m), 4.06-4.12 (1H, m), 4.84-4.94 (1H, m), 6.72-6.79

(2H, m), 7.06 (2H, d, J = 10.8 Hz), 7.18- 7.25 (3H, m), 8.04 (1H, d, J =6.2 Hz), 8.12 (1H, d, J = 6.8 Hz), 8.45 (1H, s). [M + H] Calc'd forC₂₆H₃₀N₄O₂: 431; Found: 431.

39A and (R)-3-(((6-((4-isobutylphenyl)(methyl)amino)-1,2,3,4- 10A andNMR (400 MHz, CD₃OD): δ 0.94 (6H, 39Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 10B d, J = 6.8 Hz),1.85-1.91 (1H, m), 2.49 acid; and(S)-3-(((6-((4-isobutylphenyl)(methyl)amino)- (2H, d, J = 6.8 Hz),3.03-3.10 (2H, m), 1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) 3.25(3H, s), 3.34-3.38 (1H, m), 3.62-3.66 isonicotinic acid (1H, m),3.89-3.95 (1H, m), 4.08-4.12 (1H, m), 4.85-4.88 (1H, m), 6.73-6.79

(2H, m), 7.06 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.22-7.25(1H, m), 8.05 (1H, d, J = 5.2 Hz), 8.14 (1H, d, J = 5.2 Hz), 8.47 (1H,s). [M + H] Calc'd for C₂₇H₃₂N₄O₂: 445; Found: 445.

40A and (R)-3-(((6-((4-hexylphenyl)(methyl)amino)-1,2,3,4-tetra- 10A andNMR (400 MHz, CD₃OD): δ 0.90 (3H, 40Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; 10B t, J = 7.2Hz), 1.29-1.37 (6H, m), 1.58- and(S)-3-(((6-((4-hexylphenyl)(methyl)amino)-1,2,3,4- 1.65 (2H, m), 2.60(2H, t, J = 7.2 Hz), tetra-hydroisoquinolin-1-yl)methyl)amino) 2.98-3.08(2H, m), 3.25 (3H, s), 3.34-3.38 isonicotinic acid (1H, m), 3.59-3.65(1H, m), 3.86-3.92 (1H, m), 4.05-4.10 (1H, m), 4.82-4.89

(1H, m), 6.69-6.76 (2H, m), 7.04 (2H, d, J = 8.4 Hz), 7.17-7.22 (3H, m),8.02 (1H, d, J = 5.2 Hz), 8.11 (1H, d, J = 5.2 Hz), 8.43 (1H, s). [M +H] Calc'd for C₂₉H₃₆N₄O₂: 473; Found: 473.

41A and (R)-3-(((6-((4-(cyclopropylmethyl)phenyl)(methyl) 10A and NMR(400 MHz, CD₃OD): δ 0.19-0.23 41Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 10B (2H, m), 0.50-0.54(2H, m), 0.97-1.00 amino)isonico-tinic acid; and (S)-3-(((6-((4-(cyclo-(1H, m) 2.53 (2H, d, J = 6.8 Hz), 3.01-3.08propylmethyl)phenyl)(methyl)amino)-1,2,3,4-tetra- (2H, m), 3.25 (3H, s),3.36-3.41 (1H, m), hydroisoquinolin-1-yl)methyl)amino)isonicotinic acid3.60-3.63 (1H, m), 3.86-3.92 (1H, m), 4.05-4.09 (1H, m), 4.85-4.93 (1H,m),

6.70-6.77 (2H, m), 7.05 (2H, d, J = 8.4 Hz), 7.21-7.26 (3H, m), 8.02(1H, d, J = 5.2 Hz), 8.11 (1H, d, J = 5.2 Hz), 8.44 (1H, s). [M + H]Calc'd for C₂₇H₃₀N₄O₂, 443; Found: 443.

42A and (R)-3-(((6-(methyl(4-(2,2,2-trifluoroethoxy)phenyl) 10A and NMR(400 MHz, CD₃OD): δ 3.00-3.07 42Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 10B (2H, m), 3.25 (3H,s), 3.36-3.41 (1H, m), amino)isonicotinic acid; and(S)-3-(((6-(methyl(4-(2,2,2- 3.58-3.63 (1H, m), 3.87-3.89 (1H, m),trifluoro-ethoxy)phenyl)amino)-1,2,3,4-tetrahydro- 4.03-4.06 (1H, m),4.50-4.56 (2H, m), isoquinolin-1-yl)methyl)amino)isonicotinic acid4.80-4.84 (1H, m), 6.64-6.72 (3H, m), 7.02-7.06 (2H, m), 7.11-7.14 (2H,m),

7.99 (2H, s), 8.36 (1H, s). [M + H] Calc'd for C₂₅H₂₅F₃N₄O₃: 487; Found:487.

43A and (R)-3-(((6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4- 8A andNMR (400 MHz, CD₃OD): δ 2.17-2.21 43Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 8B (4H, m), 2.28(3H, s), 3.19-3.23 (2H, m), acid; and(S)-3-(((6-(2-methyl-4-(pyrrolidin-1-yl) 3.46-3.49 (1H, m), 3.58-3.61(4H, m), phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 3.70-3.74(1H, m), 4.01-4.07 (1H, m), amino)isonicotinic acid 4.20-4.25 (1H, m),5.04-5.08 (1H, m), 7.05-7.08 (2H, m), 7.22-7.29 (3H, m),

7.53 (1H, d, J = 8.0 Hz), 8.09 (1H, d, J = 5.2 Hz), 8.30 (1H, d, J = 5.2Hz), 8.62 (1H, s). [M + H] Calc'd for C₂₇H₃₀N₄O₂: 443; Found: 443.

44A and (R)-3-(((6-((4-isopropoxyphenyl)(methyl)amino)-1,2,3,4- 10A andNMR (400 MHz, CD₃OD): δ 1.31 (6H, 44Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 10B d, J = 6.0 Hz),2.97-3.12 (2H, m), 3.22 acid; and(S)-3-(((6-((4-isopropoxyphenyl)(methyl) (3H, s), 3.34-3.40 (1H, m),3.59-3.64 amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) (1H, m),3.95-4.00 (1H, m), 4.10-4.15 amino)isonicotinic acid (1H, m), 4.50-4.54(1H, m), 4.91-4.95 (1H, m), 6.61-6.64 (2H, m), 6.91-6.93

(2H, m), 7.04-7.08 (2H, m), 7.19-7.21 (1H, m), 8.08 (1H, d, J = 5.6 Hz),8.34 (1H, d, J = 5.6 Hz), 8.59 (1H, s). [M + H] Calc'd for C₂₆H₃₀N₄O₃:447; Found: 447.

45A and (R)-3-(((6-(methyl(4-(2,2,2-trifluoroethyl)phenyl) 10A and NMR(400 MHz, CD₃OD): δ 3.04-3.10 45Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 10B (2H, m), 3.22 (3H,s), 3.37-3.48 (3H, m), amino)isonicotinic acid; and(S)-3-(((6-(methyl(4-(2,2,2- 3.62-3.66 (1H, m), 3.87-3.93 (1H, m),trifluoro-ethyl)phenyl)amino)-1,2,3,4-tetrahydroiso- 4.06-4.11 (1H, m),4.85-4.89 (1H, m), quinolin-1-yl)methyl)amino)isonicotinic acid6.86-6.92 (2H, m), 7.07-7.10 (2H, m), 7.27-7.30 (3H, m), 8.01-8.07 (2H,m),

8.42 (1H, s). [M + H] Calc'd for C₂₅H₂₅F₃N₄O₂, 471; Found, 471.

46A and (R)-3-(((6-((4-chlorophenyl)(methyl)amino)-1,2,3,4- 10A and NMR(400 MHz, CD₃OD): δ 3.04-3.10 46Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 10B (2H, m), 3.17(3H, s), 3.37-3.43 (1H, m), acid; and(S)-3-(((6-((4-chlorophenyl)(methyl)amino)- 3.61-3.66 (1H, m), 3.87-3.93(1H, m), 1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino) 4.06-4.11(1H, m), 4.90-4.95 (1H, m), isonicotinic acid 6.85-6.92 (2H, m),7.03-7.06 (2H, m), 7.27-7.31 (3H, m), 8.01-8.07 (2H, m),

8.42 (1H, s). [M + H] Calc'd for C₂₃H₂₃ClN₄O₂, 423; Found: 423.

47A and (R)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin- 8A andNMR (400 MHz, CD₃OD): δ 1.05 (3H, 47B 1-yl)methyl)amino)isonicotinicacid; and (S)-3-(((6-(2- 8B t, J = 7.6 Hz), 2.57 (2H, q, J = 7.6 Hz),ethyl-phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 3.15-3.23 (2H,m), 3.45-3.52 (1H, m), amino)isonicotinic acid 3.69-3.75 (1H, m),3.99-4.05 (1H, m), 4.18-4.23 (1H, m), 5.03-5.06 (1H, m),

7.11-7.32 (6H, m), 7.52 (1H, d, J = 8.4 Hz), 8.06 (1H, d, J = 5.2 Hz),8.16 (1H, d, J = 5.2 Hz), 8.54 (1H, s). [M + H] Calc'd for C₂₄H₂₅N₃O₂:388; Found: 388.

48A and (R)-3-(((6-(2-isopropylphenyl)-1,2,3,4-tetrahydroiso- 8A and NMR(400 MHz, CD₃OD): δ 1.16 (6H, 48Bquinolin-1-yl)methyl)amino)isonicotinic acid; and (S)-3- 8B d, J = 8.4Hz), 2.95-3.04 (1H, m), 3.19-(((6-(2-isopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1- 3.25 (2H, m),3.45-3.54 (1H, m), 3.70- yl)methyl)amino)isonicotinic acid 3.78 (1H, m),3.96-4.05 (1H, m), 4.18- 4.25 (1H, m), 5.03-5.08 (1H, m), 7.10-

7.44 (6H, m), 7.54 (1H, d, J = 10.4 Hz), 8.06 (1H, d, J = 7.2 Hz), 8.11(1H, d, J = 7.2 Hz), 8.54 (1H, s). [M + H] Calc'd for C₂₅H₂₇N₃O₂: 402;Found: 402.

49A and (R)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluoroethoxy) 8A and NMR(400 MHz, CD₃OD): δ 1.99 (3H, 49Bphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 8B s), 2.01 (3H, s),2.95-3.04 (2H, m), amino)isonicotinic acid; and(S)-3-(((6-(2,6-dimethyl-4- 3.46-3.54 (1H, m), 3.69-3.76 (1H, m),(2,2,2-trifluoro-ethoxy)phenyl)-1,2,3,4-tetrahydroiso- 3.96-4.05 (1H,m), 4.16-4.23 (1H, m), quinolin-1-yl)methyl)amino)isonicotinic acid4.49-4.57 (2H, m), 5.00-5.05 (1H, m), 6.78 (2H, s), 7.11-7.14 (2H, m),7.57

(1H, d, J = 10.8 Hz), 7.95 (1H, d, J = 6.8 Hz), 8.00 (1H, d, J = 7.2Hz), 8.45 (1H, s). [M + H] Calc'd for C₂₆H₂₆F₃N₃O₃, 486; Found, 486.

50A and (R)-3-(((6-(2-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4- 8A and NMR(400 MHz, CD₃OD): δ 3.18-3.24 50Btetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinic 8B (2H, m),3.45-3.51 (1H, m), 3.69-3.73 acid; and(S)-3-(((6-(2-(2,2,2-trifluoroethoxy)phenyl)- (1H, m), 3.96-4.02 (1H,m), 4.17-4.22 1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino) (1H, m),4.51 (2H, dd, J = 8.4 & 17.2 Hz), isonicotinic acid 5.02 (1H, dd, J =4.4 & 10.2 Hz), 7.12-

7.16 (2H, m), 7.36-7.40 (2H, m), 7.48- 7.54 (3H, m), 8.05 (1H, d, J =5.6 Hz), 8.15 (1H, d, J = 6.0 Hz), 8.54 (1H, s). [M + H] Calc'd forC₂₄H₂₂F₃N₃O₃: 458; Found: 458.

51A and (R)-3-(((6-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroiso- 8A andNMR (400 MHz, CD₃OD): δ 1.97 51B quinolin-1-yl)methyl)amino)isonicotinicacid; and (S)-3- 8B (3H, s), 1.99 (3H, s), 3.18-3.24 (2H, m),(((6-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin- 3.47-3.53 (1H,m), 3.69-3.76 (1H, m), 1-yl)methyl)amino)isonicotinic acid 4.00-4.06(1H, m), 4.18-4.22 (1H, m), 5.02-5.06 (1H, m), 7.08-7.17 (5H, m),

7.56 (1H, d, J = 8.0 Hz), 8.02-8.07 (2H, m), 8.50 (1H, s). [M + H]Calc'd for C₂₄H₂₅N₃O₂: 388; Found: 388

52A and (R)-3-(((6-(2-cyclopropylphenyl)-1,2,3,4-tetrahydroiso- 8A andNMR (400 MHz, MeOD): δ 0.66-0.69 52Bquinolin-1-yl)methyl)amino)isonicotinic acid; and 8B (2H, m), 0.79-0.82(2H, m), 1.79-1.83(S)-3-(((6-(2-cyclopropylphenyl)-1,2,3,4-tetrahydroiso- (1H, m),3.20-3.30 (2H, m), 3.48-3.51 quinolin-1-yl)methyl)amino)isonicotinicacid (1H, m), 3.70-3.74 (1H, m), 3.97-4.03 (1H, m), 4.16-4.21 (1H, m),5.01-5.04 (1H, m), 6.98 (1H, d, J = 8.0 Hz), 7.15- 7.22 (2H, m),7.25-7.29 (1H, m), 7.37- 7.41 (2H, m), 7.52 (1H, d, J = 8.0 Hz),8.02-8.06 (2H, m), 8.48 (1H, s), [M + H] Calc'd for C₂₅H₂₅N₃O₂: 400;Found 400.

53A and (R)-3-(((6-((4-(dimethylamino)phenyl)(methyl)amino)- 10A and NMR(400 MHz, MeOD): δ 3.07-3.11 53B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)iso- 10B (2H, m), 3.26(6H, s), 3.34 (3H, s), nicolinic acid; and(S)-3-(((6-((4-(dimethylamino) 3.40-3.47 (1H, m), 3.65-3.69 (1H, m),phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1- 3.96-4.04 (1H,m), 4.05-4.20 (1H, m), yl)methyl)amino)isonicotinic acid 4.98-5.06 (1H,m), 7.07-7.11 (4H, m), 7.44-7.50 (3H, m), 8.11 (1H, d, J = 5.6

Hz), 8.35 (1H, d, J = 5.2 Hz), 8.61 (1H, s). [M + H] Calc'd forC₂₅H₂₉N₅O₂: 432; Found: 432

54A and (R)-3-(((6-((4-cyclohexylphenyl)(methyl)amino)-1,2,3,4- 10A andNMR (400 MHz, MeOD): δ 1.27-1.50 54Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 10B (5H, m),1.75-1.87 (5H, m), 2.48-2.53 acid; and(S)-3-(((6-((4-cyclohexylphenyl)(methyl) (1H, m), 2.98-3.07 (2H, m),3.10 (3H, s), amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)3.34-3.40 (1H, m), 3.58-3.62 (1H, m), amino)isonicotinic acid 3.81-3.86(1H, m), 4.02-4.06 (1H, m), 4.78-4.85 (1H, m), 6.69-6.78 (2H, m),

7.05 (2H, d, J = 10.0 Hz), 7.20-7.23 (3H, m), 7.87 (1H, d, J = 5.2 Hz),7.96 (1H, d, J = 5.2 Hz), 8.33 (1H, s). [M + H] Calc'd for C₂₉H₃₄N₄O₂;471; Found: 471.

55A and (R)-3-(((6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl) 10A andNMR (400 MHz, MeOD): δ 1.75-1.83 55Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 10B (4H, m), 2.80-2.84(1H, m), 3.05-3.08 amino)isonicotinic acid; and(S)-3-(((6-(methyl(4-(tetra- (2H, m), 3.28 (3H, s), 3.53-3.56 (1H, m),hydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetrahydro- 3.57-3.64 (3H, m),3.90-3.93 (1H, m), isoquinolin-1-yl)methyl)amino)isonicotinic acid4.04-4.08 (3H, m), 4.83-4.85 (1H, m), 6.74-6.81 (2H, m), 7.10 (2H, d, J= 11.6

Hz), 7.11-7.28 (3H, m), 8.03-8.07 (2H, m), 8.42 (1H, s). [M + H] Calc'dfor C₂₈H₃₂N₄O₃: 473; Found: 473.

56A and (R)-3-(((6-(methyl(4-(3,3,3-trifluoropropyl)phenyl) 10A and NMR(400 MHz, MeOD): δ 2.43-2.50 56Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 10B (2H, m), 2.84-2.89(2H, m), 3.02-3.08 amino)isonicotinic acid; and(S)-3-(((6-(methyl(4-(3,3,3- (2H, m), 3.28 (3H, s), 3.36-3.41 (1H, m),trifluoropropyl)phenyl)amino)-1,2,3,4-tetrahydroiso- 3.61-3.65 (1H, m),3.88-3.92 (1H, m), quinolin-1-yl)methyl)amino)isonicotinic acid4.05-4.10 (1H, m), 4.83-4.85 (1H, m), 6.75-6.82 (2H, m), 7.07 (2H, d, J= 8.0

Hz), 7.23-7.25 (3H, m), 8.01-8.08 (2H, m), 8.42 (1H, s). [M + H] Calc'dfor C₂₆H₂₇F₃N₄O₂: 485; Found: 485.

57A and (R)-3-(((6-((4-(2-cyclopropylethyl)phenyl)(methyl) 10A and NMR(400 MHz, DMSO-d6): δ 0.01- 57Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl 10B 0.08 (2H, m),0.40-0.45 (2H, m), 0.69- amino)isonicotinic acid; and(S)-3-(((6-((4-(2-cyclo- 0.75 (m, 1H), 1.48-1.54 (m, 2H), 2.70propylethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydro- (2H, t, J = 8.0Hz), 3.02-3.06 (2H, m), isoquinolin-1-yl)methyl)amino)isonicotinic acid3.27 (3H, s), 3.33-3.39 (1H, m), 3.60- 3.63 (1H, m), 3.80-3.86 (lH,m),4.02-

4.06 (1H, m), 4.79-4.88 (1H, m), 6.69 (1H, d, J = 2.4 Hz), 6.76 (1H, dd,J = 8.4, 2.4 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.19-7.23 (3H, m), 7.87 (1H,d, J = 5.2 Hz), 7.96 (1H, d, J = 5.2 Hz), 8.33 (1H, s). [M+H] Calc'd forC₂₈H₃₂N₄O₂: 457; Found: 457.

58A and (R)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-1,2,3,4- 10A andNMR (400 MHz, DMSO-d6): δ 1.78- 58Btetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic 10B 2.12 (4H, m),2.24-2.33 (2H, m), 2.90- acid; and(S)-3-(((6-((4-cyclobutylphenyl)(methyl) 2.94 (2H, m), 3.23 (3H, s),3.23-3.25 amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) (1H, m),3.37-3.53 (2H, m), 3.76-3.80 amino)isonicotinic acid (1H, m), 3.99-4.03(1H, m), 4.73-4.76 (1H, m), 6.74-6.78 (2H, m), 7.03 (2H,

d, J = 8.2 Hz), 7.21 (2H, d, J = 8.2 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.68(1H, d, J = 5.2 Hz), 7.80 (1H, s), 7.96 (1H, d, J = 5.2 Hz), 8.51 (1H,s), 8.89 (1H, br), 9.39 (1H, br). [M + H] Calc'd for C₂₇H₃₀N₄O₂: 443;Found: 443.

59A and (R)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)- 10A and NMR(400 MHz, CD₃OD): δ 1.59-1.62 59B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) 10B (2H, m), 1.72-1.76(2H, m), 1.82-1.85 isonicotinic acid; and(S)-3-(((6-((4-cyclopentylphenyl) (2H, m), 2.06-2.08 (2H, m), 2.98-3.08(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) (3H, m), 3.26 (3H,s), 3.35-3.41 (1H, m), methyl)amino)isonicotinic acid 3.58-3.65 (1H, m),3.85-3.91 (1H, m), 4.04-4.09 (1H, m), 4.82-4.85 (1H, m),

6.70 (1H, s), 6.75 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.05 (2H, d, J = 8.8Hz), 7.21- 7.26 (3H, m), 8.00-8.05 (2H, m), 8.40 (1H, s). [M + H] Calc'dfor C₂₈H₃₂N₄O₂: 457; Found: 457

60A and (R)-3-(((6-((4-(cyclobutylmethyl)phenyl)(methyl) 10A and NMR(400 MHz, DMSO-d6): δ 1.67- 60Bamino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) 10B 1.82 (4H, m),1.99-2.08 (2H, m), 2.54- amino)isonicotinic acid; and(S)-3-(((6-((4-(cyclobutyl- 5.56 (1H, m), 2.64-2.67 (m, 2H), 2.92-methyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydroiso- 2.94 (m, 2H), 3.22(3H, s), 3.26-3.28 quinolin-1-yl)methyl)amino)isonicotinic acid (1H, m),3.51-3.53 (1H, m), 3.76-3.78 (1H, m), 3.98-4.02 (1H, m), 4.74-4.76

(1H, m), 6.74-6.76 (2H, m), 7.00 (2H, d, J = 8.2 Hz), 7.13 (2H, d, J =8.2 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.68 (1H, d, J = 5.2 Hz), 7.80 (1H,s), 7.96 (1H, d, J = 5.2 Hz), 8.50 (1H, s), 8.78 (1H, br), 9.27 (1H,br). [M + H] Calc'd for C₂₈H₃₂N₄O₂: 457; Found: 457.

61A and (R)-3-(((6-(6-methyl-2,3-dihydrobenzofuran-5-yl)- 8A and NMR(400 MHz, MeOD): δ 2.16 (3H, 61B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) 8B s), 3.16-3.24 (4H,m) 3.45-3.52 (1H, m), isonicotinic acid; and(S)-3-(((6-(6-methyl-2,3-dihydro- 3.69-3.74 (1H, m), 4.03-4.09 (1H, m),benzofuran-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl) 4.19-4.23 (1H, m),4.53-4.57 (2H, m), methyl)amino)isonicotinic acid 5.04-5.14 (1H, m),6.65 (1H, d, J = 8.0 Hz), 7.00 (1H, d, J = 8.0 Hz), 7.21-7.23

(2H, m), 7.48 (1H, d, J = 7.6 Hz), 8.11 (1H, d, J = 6.0 Hz), 8.36 (1H,d, J = 5.6 Hz), 8.61 (1H, s). [M + H] Calc'd for C₂₅H₂₅N₃O₃: 416; Found:416.

62A and (R)-3-(((6-(5-methyl-2,3-dihydrobenzofuran-4-yl)- 8A and NMR(400 MHz, MeOD): δ 2.03 (3H, 62B1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) 8B s), 2.88-2.92 (2H,m), 3.19-3.24 (2H, m), isonicotinic acid; and(5)-3-(((6-(5-methyl-2,3-dihydro- 3.47-3.50 (1H, m), 3.70-3.73 (1H, m),benzofuran-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl) 3.96-4.02 (1H, m),4.15-4.19 (1H, m), methyl)amino)isonicotinic acid 4.44-4.49 (2H, m),4.99-5.03 (1H, m), 6.63 (1H, d, J = 8.0 Hz), 7.00 (1H, d,

J = 8.0 Hz), 7.21-7.23 (2H, m), 7.54 (1H, d, J = 8.0 Hz), 7.97-8.01 (2H,m), 8.44 (1H, s). [M + H] Calc'd for C₂₅H₂₅N₃O₃: 416; Found: 416.

63A and (R)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)iso- 7A andNMR (300 MHz, CD3OD): δ 3.88-3.96 63Bindolin-1-yl)methyl)amino)isonicotinic acid; and 7B (1H, m), 4.12-4.18(1H, m), 4.58-4.89(S)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)iso- (4H, m),5.35-5.38 (1H, m), 6.94-6.98 indolin-1-yl)methyl)amino)isonicotinic acid(2H, m), 7.43-7.49 (1H, m), 7.64-7.56 (3H, m), 7.86-7.94 (2H, m), 8.36(1H,

s). [M + H] Calc'd for C₂₃H₁₉F₄N₃O₃: 462; Found: 462.

64A and (R)-3-(((5-(o-tolyl)isoindolin-1-yl)methyl)amino)iso- 8A and NMR(300 MHz, CD3OD): δ 2.20 (3H, 64B nicotinic acid; and(S)-3-(((5-(o-tolyl)isoindolin-1-yl)methyl) 8B s), 4.00-4.06 (1H, m),4.16-4.22 (1H, m), amino)isonicotinic acid 4.64-4.81 (2H, m), 5.40-5.43(1H, m), 7.14-7.39 (6H, m), 7.61 (1H, d, J = 7.8

Hz), 8.02 (1H, d, J = 5.4 Hz), 8.13 (1H, t, J = 5.4 Hz), 8.50 (s, 1H).[M + H] Calc'd for C₂₂H₂₁N₃O₂: 360; Found: 360.

65A and (R)-3-(((5-((4-isopropylphenyl)(methyl)amino)iso- 7A and NMR(300 MHz, CD3OD): δ 1.25 (6H, 65B indolin-1-yl)methyl)amino)isonicotinicacid; and 7B d, J = 6.6 Hz), 2.88-2.92 (1H, m), 3.26(S)-3-(((5-((4-isopropylphenyl)(methyl)amino) (3H, s), 3.85-3.88 (1H,m), 4.00-4.02 isoindolin-1-yl)methyl)amino)isonicotinic acid (1H, m),4.45-4.57 (2H, m), 5.17-5.20 (1H, m), 6.80-6.83 (2H, m), 7.05 (2H, d,

J = 8.4 Hz), 7.22-7.30 (3H, m), 7.93-7.95 (2H, m), 8.33 (1H, s). [M + H]Calc'd for C₂₅H₂₈N₄O₂: 417; Found: 417.

66A and (R)-3-(((5-(4-isopropyl-2-methylphenyl)isoindolin-1-yl) 7A andNMR (400 MHz, MeOD): δ 0.88 (6H, 66B methyl)amino)isonicotinic acid; and(S)-3-(((5-(4-iso- 7B d, J = 9.2 Hz), 2.16 (3H, s), 2.87-2.91propyl-2-methylphenyl)isoindolin-1-yl)methyl)amino) (1H, m), 3.93-3.99(1H, m), 4.13-4.16 isonicotinic acid (1H, m), 4.64-4.77 (2H, m),5.35-5.36 (1H, m), 7.05-7.13 (3H, m), 7.34-7.36

(2H, m), 7.57-7.59 (1H, m), 7.91-7.95 (2H, m), 8.40 (1H, s). [M + H]Calc'd for C₂₅H₂₇N₃O₂: 402; Found: 402.

67A and (R)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)iso- 5A and NMR(400 MHz, MeOD): δ 0.63-0.67 67B indolin-1-yl)methyl)amino)isonicotinicacid; and 5B (2H, m), 0.93-0.98 (2H, m), 1.88-1.92(S)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)iso- (1H, m), 3.25 (3H,s), 3.81-3.86 (1H, m), indolin-1-yl)methyl)amino)isonicotinic acid4.01-4.05 (1H, m), 4.46-4.60 (2H, m), 5.17-5.20 (1H, m), 6.78-6.82 (2H,m),

7.00 (2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.8 Hz), 7.27 (1H, d, J = 8.0Hz), 7.93 (2H, s), 8.32 (1H, s). [M + H] Calc'd for C₂₅H₂₆N₄O₂: 415;Found: 415.

68A and (R)-3-(((5-((4-ethylphenyl)(methyl)amino)isoindolin-1- 5A andNMR (400 MHz, MeOD): δ 1.24 (3H, t, 68B yl)methyl)amino)isonicotinicacid; and 5B J = 8.0 Hz), 2.63 (2H, q, J = 8.0 Hz), 3.26(S)-3-(((5-((4-ethylphenyl)(methyl)amino)isoindolin-1- (3H, s),3.81-3.86 (1H, m), 4.00-4.05 yl)methyl)amino)isonicotinic acid (1H, m),4.46-4.60 (2H, m), 5.17-5.19 (1H, m), 6.79-6.83 (2H, m), 7.03 (2H, d,

J = 8.4 Hz), 7.21 (2H, d, J = 8.8 Hz), 7.28 (1H, d, J = 8.4 Hz),7.89-7.94 (2H, m), 8.30 (1H, s). [M + H] Calc'd for C₂₅H₂₃F₃N₂O₄: 473;Found: 473.

69A and (R)-3-(((5-(methyl(4-propylphenyl)amino)isoindolin-1- 5A and NMR(400 MHz, MeOD): δ 0.95 (3H, 69B yl)methyl)amino)isonicotinic acid; and5B t, J = 8.0 Hz), 1.61-1.67 (2H. m), 2.56-(S)-3-(((5-(methyl(4-propylphenyl)amino)isoindolin-1- 2.60 (2H, m), 3.26(3H, s), 3.80-3.85 yl)methyl)amino)isonicotinic acid (1H, m), 4.00-4.05(1H, m), 4.46-4.61 (2H, m), 5.16-5.19 (1H, m), 6.80-6.83

(2H, m), 7.03 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.28 (1H,d, J = 8.0 Hz), 7.86-7.92 (2H, m), 8.28 (1H, s). [M + H] Calc'd forC₂₅H₂₈N₄O₂: 417; Found: 417.

70A and (R)-3-(((5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)iso- 7A and NMR(400 MHz, MeOD): δ 2.06-2.11 70B indolin-1-yl)methyl)amino)isonicotinicacid; and (S)-3- 7B (4H, m), 2.21 (3H, s), 3.40-3.42 (4H,(((5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)isoindolin-1-yl) m), 3.98-4.03(1H, m), 4.15-4.19 (1H, methyl)amino)isonicotinic acid m), 4.64-4.78(2H, m), 5.38-5.40 (1H, m), 6.70-6.73 (2H, m), 7.08 (1H, d, J =

8.0 Hz), 7.34-7.36 (2H, m), 7.56 (1H, d, J = 8.4 Hz), 8.02 (1H, s),8.16-8.18 (1H, m), 8.50 (1H, s). [M + H] Calc'd for C₂₆H₂₈N₄O₂: 429;Found: 429.

71A and (R)-3-(((5-(2-ethylphenyl)isoindolin-1-yl)methyl)amino) 7A andNMR (300 MHz, MeOD): δ 1.04 (3H, 71B isonicotinic acid; and(S)-3-(((5-(2-ethylphenyl)iso- 7B t, J = 7.5 Hz), 2.54 (2H, q, J = 7.5Hz), indolin-1-yl)methyl)amino)isonicotinic acid 3.99-4.06 (1H, m),4.15-4.22 (1H, m), 4.67-4.82 (2H, m), 5.40-5.43 (1H, m),

7.12 (1H, d, J = 7.5 Hz), 7.22-7.26 (1H, m), 7.32-7.38 (4H, m), 7.62(1H, d, J = 7.8 Hz), 8.00-8.08 (2H, m), 8.47 (1H, s). [M + H] Calc'd forC₂₃H₂₃N₃O₂: 374; Found: 374.

72A and (R)-3-(((5-(2-isopropylphenyl)isoindolin-1-yl)methyl) 7A and NMR(400 MHz, MeOD): δ 1.12 (6H, d, 72B amino)isonicotinic acid; and(S)-3-(((5-(2-isopropyl 7B J = 4.4 Hz), 2.86-5.89 (1H, m), 3.99-4.03phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid (1H, m), 4.13-4.17(1H, m), 4.66-4.79 (2H, m), 5.36-5.39 (1H, m), 7.06 (1H,

d, J = 8.0 Hz), 7.17-7.21 (1H, m), 7.31- 7.41 (4H, m), 7.60 (1H, d, J =7.6 Hz), 7.93-7.96 (2H, m), 8.40 (1H, s). [M + H] Calc'd C₂₄H₂₅N₃O₂:388; Found: 388.

73A and (R)-3-(((5-(2-cyclopropylphenyl)isoindolin-1-yl)methyl) 7A andNMR (300 MHz, MeOD): δ 0.64-0.69 73B amino)isonicotinic acid; and(S)-3-(((5-(2-cyclopropyl 7B (2H, m), 0.77-0.84 (2H, m), 1.70-1.74phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid (1H, m), 3.99-4.06(1H, m), 4.15-4.21 (1H, m), 4.67-4.82 (2H, m), 5.39-5.42 (1H, m), 7.00(1H, d, J = 7.2 Hz), 7.14-

7.31 (3H, m), 7.48-7.49 (2H, m), 7.61- 7.64 (1H, m), 7.96-8.01 (2H, m),8.43 (1H, s). [M + H] Calc'd for C₂₄H₂₃N₃O₂: 386; Found: 386

II. Biological Evaluation

Example 1A In Vitro Enzyme Inhibition Assay for JMJD2C Activity

This assay determines the ability of a test compound to inhibit JMJD2Cdemethylase activity. Baculovirus expressed JMJD2C (GenBank Accession #BC143571, AA 2-372) was purchased from BPS Bioscience (Cat #50105).

JMJD2C Assay

The ability of test compounds to inhibit the activity of JMJD2C wasdetermined in 384-well plate format under the following reactionconditions: 0.3 nM JMJD2C, 300 nM H3K9me3-biotin labeled peptide(Anaspec cat #64360), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-di-methylated histone H3 lysine 9 (H3K9me2) antibody(PerkinElmer) in the presence of 5 mM EDTA in LANCE detection buffer(PerkinElmer) at a final concentration of 50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K9me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of 0.9nM JMJD2C to initiate the reaction. The reaction mixture was incubatedat RT for 30 min, and terminated by the addition of 6 μl of 5 mM EDTA inLANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K9me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at RT. A ratio was calculated (665/615) for each well andfitted to determine inhibition constant (IC₅₀).

Example 1B In Vitro Enzyme Inhibition Assay for JMJD3 Activity

This assay determines the ability of a test compound to inhibit JMJD3demethylase activity. Baculovirus expressed JMJD3 (GenBank Accession #NM-001080424, AA1043-end) was purchased from BPS Bioscience (Cat#50115).

JMJD3 Assay

The enzymatic assay of JMJD3 activity is based upon TimeResolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. Theability of test compounds to inhibit the activity of JMJD3 wasdetermined in 384-well plate format under the following reactionconditions: 5 nM JMJD3, 250 nM H3K27me3-biotin labeled peptide (Anaspeccat #64367), 0.4 to 2 μM α-ketoglutaric acid in assay buffer of 50 mMHEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 5 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-H3K27me2 antibody (PerkinElmer) in the presence of 5 mMEDTA in LANCE detection buffer (PerkinElmer) at a final concentration of50 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 750 nM H3K27me3-biotin labeled peptide and 1.2 to 6 μMalpha-ketoglutaric acid with 2 μL of 11-point serial diluted inhibitorin 3% DMSO were added to each well of plate, followed by the addition of2 μl of 15 nM JMJD3 to initiate the reaction. The reaction mixture wasincubated at RT for 30 min, and terminated by the addition of 6 μL of 5mM EDTA in LANCE detection buffer containing 100 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K27me2 antibody.Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at RT. A ratio from the readout of 665/615 was calculated foreach well and fitted to determine inhibition constant (IC₅₀).

Example 1C In Vitro Enzyme Inhibition Assay for Jarid1B Activity

Jarid1B Assay

The ability of test compounds to inhibit the activity of Jarid1B wasdetermined in 384-well plate format under the following reactionconditions: 0.8 nM Jarid1B, 300 nM H3K4me3-biotin labeled peptide(Anaspec cat #64357), 2 μM alpha-ketoglutaric acid in assay buffer of 50mM HEPES, pH7.3, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA, 50 μM sodiumL-ascorbate, and 2 μM ammonium iron(II) sulfate. Reaction product wasdetermined quantitatively by TR-FRET after the addition of detectionreagent Phycolink Streptavidin-allophycocyanin (Prozyme) andEuropium-anti-H3K4me or -H3K4me2 antibody (PerkinElmer) in the presenceof 5 mM EDTA in LANCE detection buffer (PerkinElmer) at a finalconcentration of 25 nM and 1 nM, respectively.

The assay reaction was initiated by the following: 2 μl of the mixtureof 900 nM H3K4me3-biotin labeled peptide and 6 μM alpha-ketoglutaricacid with 2 μl of 11-point serial diluted inhibitor in 3% DMSO was addedto each well of the plate, followed by the addition of 2 μl of 2.4 nMJarid1B to initiate the reaction. The reaction mixture was incubated atRT for 30 min, and terminated by the addition of 6 μl of 5 mM EDTA inLANCE detection buffer containing 50 nM PhycolinkStreptavidin-allophycocyanin and 2 nM Europium-anti-H3K4me/H3K4me2antibody. Plates were read by EnVisionMultilabel Reader in TR-FRET mode(excitation at 320 nm, emission at 615 nm and 665 nm) after 1 hrincubation at RT. A ratio was calculated (665/615) for each well andfitted to determine inhibition constant (IC₅₀).

The ability of the compounds disclosed herein to inhibit demethylaseactivity was quantified and the respective IC₅₀ value was determined.Tables 4 and 5 provide IC₅₀ values of various compounds disclosed herein(“Example” refers to the chemical synthesis example as above):

TABLE 4 JMJD2C JMJD3 Jarid1b IC50 IC50 IC50 Example Name (nM) (nM) (nM)1A and 1B 3-[({(1S)-6-[methyl(4-methylphenyl)amino]- B/B* B/B A/A1,2,3,4-tetrahydroisoquinolyl}methyl)amino] pyridine-4-carboxylic acid;and 3-[({(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino] pyridine-4-carboxylic acid2A and 2B 3-[({(1S)-6-[2-methyl-4-(2,2,2-trifluoroethoxy) C/C C/C A/Aphenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylic acid; and3-[({(1R)-6-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylic acid 3A and 3B3-[({(1S)-6-{methyl[4-(methylethyl)phenyl]amino}- B/B C/B A/A1,2,3,4-tetrahydroisoquinolyl)methyl]amino} pyridine-4-carboxylic acid;and 3-[({(1R)-6- [methyl[4-(methylethyl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolyl)methyl]amino}pyridine-4- carboxylic acid 4A and 4B3-[({(1S)-6-[4-(cyclopropylmethoxy)-2-methyl- C/C C/D A/Aphenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylic acid; and3-[({(1R)-6-[4-(cyclopropylmethoxy)-2-methyl-phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylic acid 5A and 5B3-[({(1S)-5-[methyl(4-methylphenyl)amino]iso- C/B B/B A/Aindolinyl}methyl)amino] pyridine-4-carboxylic acid; and3-[({(1R)-5-[methyl(4-methylphenyl)amino]iso-indolinyl}methyl)amino]pyridine-4-carboxylic acid 6A and 6B3-[({(1S)-5-{methyl[4-(methylethyl)phenyl]amino} C/C C/D A/Aisoindolinyl)methyl]amino}pyridine-4 carboxylic acid; and3-[({(1R)-5-{methyl[4-(methylethyl)phenyl]amino}isoindolinyl)methyl]amino}pyridine-4-carboxylic acid 7A and 7B3-[({(1S)-5-[2-methyl-4-(2,2,2-trifluoroethoxy) C/C B/C A/Aphenyl]isoindolinyl}methyl)amino] pyridine-4- carboxylic acid; and3-[({(1R)-5-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]isoindolinyl}methyl)amino] pyridine-4- carboxylic acid*Biochemical assay IC₅₀ data are designated within the following ranges:A: ≤ 100 nM; B: > 100 nM to ≤ 1000 nM; C: > 1000 nM to ≤ 10,000 nM; D: >10,000 nM

TABLE 5 JMJD2C JMJD3 Jarid1b Example Compound Name IC₅₀ (nM) IC₅₀ (nM)IC₅₀ (nM)  1A 3-[({(1S)-6-[methyl(4-methylphenyl)amino]-1,2,3,4- B* C Aand 1B tetra-hydroisoquinolyl}methyl)amino]pyridine-4- carboxylic acid;and 3-[({(1R)-6-[methyl(4-methyl-phenyl)amino]-1,2,3,4-tetrahydroisoquinolyl} methyl) amino]pyridine-4-carboxylic acid  2A3-[({(1S)-6-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]- C C A and 2B1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4- carboxylic acid;and 3-[({(1R)-6-[2-methyl-4-(2,2,2-tri-fluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylic acid  3A3-{[((1S)-6-{methyl[4-(methylethyl)phenyl]amino}- B B A and 3B1,2,3,4-tetrahydroisoquinolyl)methyl]amino}pyridine-4- carboxylic acid;and 3-{[((1R)-6-{methyl[4-(methylethyl)phenyl]amino}-1,2,3,4-tetrahydroisoquinolyl)methyl]amino}pyridine-4-carboxylic acid  4A3-[({(1S)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]- B D A and 4B1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4- carboxylic acid;and 3-[({(1R)-6-[4-(cyclopropyl-methoxy)-2-methylphenyl]-1,2,3,4-tetrahydro- isoquinolyl}methyl)amino]pyridine-4-carboxylic acid  5A3-[({(1S)-5-[methyl(4-methylphenyl)amino]iso- C C A and 5Bindolinyl}methyl)amino]pyridine-4-carboxylic acid; and3-[({(1R)-5-[methyl(4-methylphenyl)amino]iso-indolinyl}methyl)amino]pyridine-4-carboxylic acid  6A3-{[((1S)-5-{methyl [4-(methylethyl)phenyl]amino} C C A and 6Bisoindolinyl)methyl]amino}pyridine-4-carboxylic acid; and3-{[((1R)-5-{methyl[4-(methylethyl)phenyl]amino}isoindolinyl)methyl]amino}pyridine-4-carboxylic acid  7A3-[({(1S)-5-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl] C C A and 7Bisoindolinyl}methyl)amino]pyridine-4-carboxylic acid; and3-[({(1R)-5-[2-methyl-4-(2,2,2-trifluoroethoxy) phenyl]isoindolinyl}methyl)amino]pyridine-4- carboxylic acid  8A(R)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) C C A and 8Bmethyl)amino)isonicotinic acid; and (S)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid  9A(R)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydroiso- C C A and 9Bquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydro- isoquinolin-1-yl)methyl)amino) isonicotinic acid 10A(R)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetra- C C A and 10Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino) isonicotinic acid. 11A(R)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4- B C A and 11Btetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino) isonicotinic acid 12A(R)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydroiso- C C A and 12 Bquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid 13A(R)-3-(((6-((4-ethylphenyl)(methyl)amino)-2- B C A and 13Bmethyl-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonico-tinicacid; and (S)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid 14A (R)-3-(((2-methyl-6-(methyl(4-propylphenyl)amino)- C C A and14B 1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;and (S)-3-(((2-methyl-6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid 15A(R)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydro- B C A and 15Bisoquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid 16A(R)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetra- C — A and 16Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid 17A(R)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetra- C — A and 17Bhydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino) isonicotinic acid 18A(R)-3-(((2-methyl-5-(methy](p-tolyl)amino)iso- B C A and 18Bindolin-1-yl)methyl)amino)isonicotmic acid; and(S)-3-(((2-methyl-5-(methyl(p-tolyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 19A(R)-3-(((5-((4-ethylphenyl)(methyl)amino)-2-methyl- B C A and 19Bisoindolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((5-((4-ethylphenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid 20A(R)-3-(((2-methyl-5-(methyl(4-propylphenyl)amino)iso- B C A and 20Bindolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((2-methyl-5-(methyl(4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid 21A(R)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl)methyl) B C A and 21Bamino) isonicotinic acid; and (S)-3-(((2-methyl-5-(o-tolyl)iso-indolin-1-yl)methyl)amino) isonicotinic acid 22A(R)-3-(((5-(2-ethylphenyl)-2-methylisoindolin-1-yl) B C A and 22Bmethyl)amino)isonicotinic acid; and(S)-3-(((5-(2-ethylphenyl)-2-methylisoindolin-1-yl) methyl)amino)isonicotinic acid *Biochemical assay IC₅₀ data are designated within thefollowing ranges: A: ≤100 nM; B: >100 nM to ≤1000 nM; C: >1000 nM to≤10,000 nM; D: >10,000 nM.

Example 2 In Vitro Cell-Based Assay

The Jurkat (T-ALL) cell line proliferation assay (Cell-MTS Assay) is acolorimetric cellular assay to assess the ability of KDM small moleculeinhibitors to effect the proliferation of the established human acute Tcell leukemia cancer cell line Jurkat.

This Cell-MTS assay is a 7-day plate-based colorimetric assay whichquantifies the amount of newly generated NADH in the presence andabsence of test compound. These NADH levels are used as a proxy for thequantification of cancer cell proliferation.

Assay Method

The established cancer cell line Jurkat with a verified p53 mutationwere purchased from American Type Culture Collection (ATCC) androutinely passaged according to ATCC published protocols. For routineassay these cells were seeded at a density of 10,000 cells per 96-well.24 hr after plating, cells received an 11-point dilution of testcompound with final concentration ranges from 10 μM to 0.15 nM. Cellswere incubated in the presence of compound for 168 hr at 37° C., 5% CO₂.At the end of this compound incubation period, 80 μl of media is removedand 20 μL of CellTiter 96® AQueous Non-Radioactive Cell ProliferationAssay solution (Promega) is added. The cells were incubated until theOD₄₉₀ reached >0.6. IC₅₀ values are calculated using the IDBS XLfitsoftware package and include background subtracted OD490 values andnormalization to DMSO controls. Cellular proliferation IC₅₀ values areuploaded and archived using the Chem Biography Platform.

Table 6 provides the cellular IC₅₀ values of various compounds disclosedherein:

TABLE 6 Example Cellular IC50 (μM) 1A and 1B A/ND 2A and 2B B/B 3A and3B A/ND 4A and 4B ND/ND 5A and 5B ND/ND 6A and 6 B ND/ND 7A and 7B ND/ND*Biochemical assay IC50 data are designated within the following ranges:A: ≤0.10 μM; B: >0.10 μM to ≤1.0 μM; C: >1.0 μM to ≤10 μM; D: >10 μM;ND: not determined

Table 7 provides IC₅₀ values of various compounds disclosed herein,tested in cellular human esophageal squamous cell carcinoma KYSE-150cells:

TABLE 7 Example Cellular IC₅₀ (μM) 1A and 1B C 2A and 2B D 3A and 3B A4A and 4B B 5A and 5B C 6A and 6 B B 7A and 7B B 8A and 8B B 9A and 9B B10A and 10B B 11A and 11B A 12A and 12B A 13A and 13B A 14A and 14B A15A and 15B — 16A and 16B — 17A and 17B — 18A and 18B A 19A and 19B A20A and 20B A 21A and 21B A 22A and 22B A Cellular assay IC₅₀ data aredesignated within the following ranges: A: ≤0.10 μM; B: >0.10 μM to ≤1.0μM; C: >1.0 μM to ≤10 μM; D: >10 μM.

Example 3 In Vivo Xenograph Study

Time release pellets containing 0.72 mg 17-β Estradiol aresubcutaneously implanted into nu/nu mice. MCF-7 cells are grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells are spun down andre-suspended in 50% serum free RPMI and 50% Matrigel at 1×10⁷ cells/mL.MCF-7 cells are subcutaneously injected (100 μL/animal) on the rightflank 2-3 days post pellet implantation and tumor volume(length×width²/2) is monitored bi-weekly. When tumors reach an averagevolume of ˜200 mm³ animals are randomized and treatment is started.Animals are treated with vehicle or test compound daily for 4 weeks.Tumor volume and body weight are monitored bi-weekly throughout thestudy. At the conclusion of the treatment period, plasma and tumorsamples are taken for pharmacokinetic and pharmacodynamic analyses,respectively.

III. Preparation of Pharmaceutical Dosage Forms

Example 1 Oral Tablet

A tablet is prepared by mixing 48% by weigh of at least one compound ofFormula 1, Formula 2, Formula 3 or Formula 4; 45% by weight ofmicrocrystalline cellulose; 5% by weight of low-substitutedhydroxypropyl cellulose; and 2% by weight of magnesium stearate. Tabletsare prepared by direct compression. The total weight of the compressedtablets is maintained at 250-500 mg.

We claim:
 1. A compound, or a pharmaceutically acceptable salt thereof,selected from the group consisting of:3-[({(1S)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylicacid; 3-[({(1R)-6-[methyl(4-methylphenyl)amino]-1,2,3,4-tetrahydroisoquinolyl methyl)amino]pyridine-4-carboxylicacid;3-[({(1S)-6-[2-methyl-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,2,3,4-tetrahydro-isoquinolyl}methyl)amino]pyridine-4-carboxylicacid;3-[({(1R)-6-[2-methyl-4-(2,2,2-trifluoroethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolyl}methyl)amino]pyridine-4-carboxylic acid; 3-{[((1S)-6-{methyl[4-isopropylphenyl]amino}-1,2,3,4-tetrahydro-isoquinolyl)methyl]amino}pyridine-4-carboxylicacid; 3-{[((1R)-6-{methyl[4-isopropylphenyl]amino}-1,2,3,4-tetrahydroisoquinolyl) methyl]amino}pyridine-4-carboxylicacid;3-[({(1S)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]-1,2,3,4-tetrahydro-isoquinolyl}methyl)amino]pyridine-4-carboxylicacid;3-[({(1R)-6-[4-(cyclopropylmethoxy)-2-methylphenyl]-1,2,3,4-tetrahydroiso-quinolyl}methyl)amino]pyridine-4-carboxylic acid; 3-[({(1S)-5-[methyl(4-tolyl)amino]isoindolinyl}methyl)amino] pyridine-4-carboxylic acid;3-[({(1R)-5-[methyl(4-tolyl)amino] isoindolinyl}methyl)amino]pyridine-4-carboxylic acid; 3-{[((1S)-5-{methyl[4-isopropylphenyl]amino}isoindolinyl)methyl]amino} pyridine-4-carboxylic acid;3-{[((1R)-5-{methyl[4-isopropylphenyl] amino}isoindolinyl)methyl]amino}pyridine-4-carboxylic acid;3-[({(1S)-5-[2-methyl-4-(2,2,2-trifluoro-ethoxy)phenyl]isoindolinyl}methyl) amino]pyridine-4-carboxylic acid;3-[({(1R)-5-[2-methyl-4-(2,2,2-trifluoro-ethoxy)phenyl]isoindolinyl}methyl)amino]pyridine-4-carboxylic acid; (R)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-((4-ethylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid; (R)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((2-methyl-6-(methyl(p-tolyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid;(R)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-6-(o-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-ethylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl) methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-6-(methyl (4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid; (S)-3-(((2-methyl-6-(methyl (4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid;(R)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-ethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-isopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2,6-dimethylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-5-(methyl(p-tolyl)amino)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-5-(methyl(p-tolyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-((4-ethylphenyl)(methyl)amino)-2-methylisoindolin-1-yl) methyl)amino)isonicotinic acid;(S)-3-(((5-((4-ethylphenyl)(methyl) amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-5-(methyl(4-propylphenyl)amino)isoindolin-1-yl) methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-5-(methyl (4-propylphenyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinicacid; (S)-3-(((2-methyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-ethylphenyl)-2-methyl-isoindolin-1-yl) methyl)amino)isonicotinic acid; (S)-3-(((5-(2-ethylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino) isonicotinic acid;3-({[(1R)-6-(thiol-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid;3-({[(1S)-6-(thiol-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid;3-({[(1R)-6-[2-fluoro-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-1-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(1S)-6-[2-fluoro-4-(2,2,2-trifluoro-ethoxy)phenyl]-1,2,3,4-tetrahydroiso-quinolin-1-yl]methyl}amino)pyridine-4-carboxylicacid;3-({[(1R)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid;3-({[(1S)-6-(2,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]methyl}amino)pyridine-4-carboxylic acid;(R)-3-(((6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-chloro-2-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-isopropoxy-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-isopropoxy-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-isopropyl-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-isopropyl-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)-1,2,3,4-tetrahydroisoquino-lin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)-1,2,3,4-tetrahydroisoquino-lin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-chloro-3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-fluoro-6-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-fluoro-6-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-methyl-4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-methyl-4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-methyl-4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-methyl-4-(3,4-dihydroisoquinolin-2(1H)-yl)phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((6-(4-isopropyl-2-methoxy-phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-(4-isopropyl-2-methoxy-phenyl)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((6-(2-methyl-4-(6-methyl-indolin-1-yl)phenyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-methyl-4-(6-methyl-indolin-1-yl)phenyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-cyclopropylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-cyclopropylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(methyl(4-propylphenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-isobutylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-isobutylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-hexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-((4-hexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((6-((4-(cyclopropylmethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-(cyclopropylmethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(methyl(4-(2,2,2-trifluoroethoxy)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(methyl(4-(2,2,2-trifluoroethoxy)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinicacid; (S)-3-(((6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((6-((4-isopropoxyphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-isopropoxyphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(methyl(4-(2,2,2-trifluoro-ethyl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(methyl(4-(2,2,2-trifluoro-ethyl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-chlorophenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-((4-chlorophenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-ethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-isopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-isopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-(2-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-(2-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((6-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2,6-dimethylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-cyclopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-cyclopropylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-(dimethylamino)phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-(dimethylamino) phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-cyclohexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-((4-cyclohexylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino))-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(methyl(4-(3,3,3-trifluoropropyl)phenyl)amino)-)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(methyl(4-(3,3,3-trifluoropropyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-(2-cyclopropylethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-(2-cyclopropylethyl)phenyl) (methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-((4-(cyclobutylmethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-(cyclobutylmethyl)phenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(6-methyl-2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(6-methyl-2,3-dihydrobenzofuran-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(5-methyl-2,3-dihydrobenzofuran-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(5-methyl-2,3-dihydrobenzofuran-4-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-((4-isopropylphenyl)(methyl)amino)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((5-((4-isopropylphenyl)(methyl)amino)isoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((5-(4-isopropyl-2-methylphenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-isopropyl-2-methylphenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)isoindolin-1-yl)methyl) amino)isonicotinic acid;(S)-3-(((5-((4-cyclopropylphenyl) (methyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-((4-ethylphenyl)(methyl)amino)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((5-((4-ethylphenyl)(methyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-(methyl(4-propylphenyl) amino)isoindolin-1-yl)methyl) amino)isonicotinic acid;(S)-3-(((5-(methyl(4-propylphenyl) amino)isoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl) amino)isonicotinic acid;(S)-3-(((5-(2-methyl-4-(pyrrolidin-1-yl) phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-ethylphenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((5-(2-ethylphenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((5-(2-isopropylphenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((5-(2-isopropylphenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((5-(2-cyclopropylphenyl) isoindolin-1-yl)methyl)amino)isonicotinic acid; and (S)-3-(((5-(2-cyclopropylphenyl)isoindolin-1-yl)methyl)amino) isonicotinic acid.
 2. A pharmaceuticalcomposition comprising the compound of claim 1 and at least onepharmaceutically acceptable excipient.
 3. A compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of:(S)-3-(((6-(thiol-3-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(thiol-3-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(o-tolyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-(difluoromethyl)-2-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-(difluoromethyl)-2-methyl-phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(5-methylindolin-1-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(5-methylindolin-1-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((1′,2′,3,3′,4,4′-hexahydro-1H-[2,6′-bi-isoquinolin]-1′-yl)methyl)amino)isonicotinic acid;(R)-3-(((1′,2′,3,3′,4,4′-hexahydro-1H-[2,6′-bi-isoquinolin]-1′-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-chloro-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-chloro-3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-((6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methoxy)isonicotinic acid;(R)-3-((6-(methyl(p-tolyl)amino)-1,2,3,4-tetra-hydroisoquinolin-1-yl)methoxy)isonicotinicacid; (S)-3-((6-((4-isopropylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy) isonicotinic acid;(R)-3-((6-((4-isopropylphenyl)(methyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl)methoxy) isonicotinic acid;(S)-3-((6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methoxy)isonicotinic acid;(R)-3-((6-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1l-yl) methoxy)isonicotinic acid;(S)-3-(((6-(p-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((6-(p-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(o-tolyloxy)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(o-tolyloxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((6-(4-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinicacid; (S)-3-(((6-(2-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-fluorophenoxy)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(p-tolylthio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(p-tolylthio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(o-tolylthio)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((6-(o-tolylthio)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((6-((4-fluorophenyl)thio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-((4-fluorophenyl)thio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-((2-fluorophenyl)thio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-((2-fluorophenyl)thio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-methyl-4-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-methyl-4-phenoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2,4-difluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((5-(2,4-difluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((5-(4-chloro-2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((5-(4-chloro-2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((5-(2-methyl-4-phenoxyphenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((5-(2-methyl-4-phenoxyphenyl)isoindolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((7-(methyl(p-tolyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((7-(methyl(p-tolyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((7-((4-isopropylphenyl)(methyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((7-((4-isopropylphenyl)(methyl)amino)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((7-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinicacid;(R)-3-(((7-(2-methyl-4-(2,2,2-trifluoroethoxy)phenyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-yl)methyl)amino)isonicotinic acid;3-[({(1S)-6-[4-(cyclopropylmethoxy)-2-methyl-phenyl]-1,2,3,4-tetrahydroisoquinol-yl)}methyl)amino]pyridine-4-carboxylic acid;3-[({(1R)-6-[4-(cyclopropylmethoxy)-2-methyl-phenyl]-1,2,3,4-tetrahydroisoquinol-yl}methyl) amino]pyridine-4-carboxylic acid;(R)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-methylisoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-2-methylisoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((5-((4-isopropylphenyl)methyl)amino-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-((4-isopropylphenyl)methyl)amino-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-((4-isopropyl-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-((4-isopropyl-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-((4-cyclopropylphenyl)(methyl)amino)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-5-(2-methyl-4-(pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((5-(2-isopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2-isopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-cyclopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2-cyclopropylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(4-fluoro-2-methylphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-fluoro-2-methylphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-methoxyphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2-methoxyphenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-fluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((5-(2-fluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((5-(2,4-difluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2,4-difluorophenyl)-2-methyliso-indolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(4-cyclopropylmethoxy)-2-fluoro-phenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-cyclopropylmethoxy)-2-fluoro-phenyl)-2-methylisoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((5-(2-fluoro-4-methoxyphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2-fluoro-4-methoxyphenyl)-2-methyl-isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(4-methoxyphenyl-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-methoxyphenyl-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(4-(dimethylamino)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-(dimethylamino)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(4-(azetidin-1-yl)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-(azetidin-1-yl)-2-methylphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((2-ethyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-ethyl-5-(o-tolyl)isoindolin-1-yl) methyl)amino)isonicotinicacid; (R)-3-(((2-ethyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-ethyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-isopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-isopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-cyclopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-cyclopropyl-5-(o-tolyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-cyclopropyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-cyclopropyl-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(2-fluorophenyl)-2-isopropyliso-indolin-1-yl)methyl)amino)isonicotinicacid;(S)-3-(((5-(2-fluorophenyl)-2-isopropyliso-indolin-1-yl)methyl)amino)isonicotinicacid; (R)-3-(((2-(cyclopropylmethyl)-5-(2-fluorophenyl)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-(cyclopropylmethyl)-5-(2-fluorophenyl) isoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((2-methyl-5-(2-pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-5-(2-pyrrolidin-1-yl)phenyl)isoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((5-(2-dimethylamino)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(2-dimethylamino)phenyl)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(4-isopropyl-2-methoxyphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((5-(4-isopropyl-2-methoxyphenyl)-2-methylisoindolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-5-(p-tolyloxy)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-5-(p-tolyloxy)isoindolin-1-yl) methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-5-(p-tolylthio)isoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-5-(p-tolylthio)isoindolin-1-yl) methyl)amino)isonicotinic acid;(R)-3-(((5-ethyl(p-tolyl)amino)-2-methyliso-indolin-1-yl)methyl) amino)isonicotinic acid;(S)-3-(((5-ethyl(p-tolyl)amino)-2-methyliso-indolin-1-yl)methyl) amino)isonicotinic acid;(R)-3-(((2-methyl-5-(p-tolyl(2,2,2-trifluoro-ethyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-5-(p-tolyl(2,2,2-trifluoro-ethyl)amino)isoindolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((5-(cyclopropylmethyl)(p-tolyl)amino)-2-methylisoindolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((5-(cyclopropylmethyl)(p-tolyl)amino)-2-methylisoindolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((2-methyl-6-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-6-(thiophen-3-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-(2-fluoro-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-(2-fluoro-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2,4-difluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2,4-difluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-chloro-2-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-chloro-2-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-isopropoxy-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-(4-isopropoxy-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((6-(4-isopropyl-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-isopropyl-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-(4-(difluoromethoxy)-2-methylphenyl)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((2-methyl-6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-6-(2-methyl-4-propoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-chloro-3-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(4-chloro-3-fluorophenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-fluoro-6-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((6-(2-fluoro-6-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(4-isopropyl-2-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-(4-isopropyl-2-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid; (R)-3-(((6-(4-cyclopropylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl) methyl)amino)isonicotinic acid; (S)-3-(((6-(4-cyclopropylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-(4-isobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl) methyl)amino)isonicotinic acid; (S)-3-(((6-(4-isobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl) methyl)amino)isonicotinic acid; (R)-3-(((6-(4-cyclopropylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-(4-cyclopropylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluoro-ethoxy)phenyl)amino)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluoro-ethoxy)phenyl)amino)-)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((2-methyl-6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino) isonicotinicacid; (S)-3-(((2-methyl-6-(2-methyl-4-(pyrrolidin-1-yl)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino) isonicotinicacid;(R)-3-(((6-(4-isopropoxyphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-(4-isopropoxyphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluroethyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid; (S)-3-(((2-methyl-6-(methyl(4-(2,2,2-trifluroethyl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino)isonicotinic acid;(R)-3-(((6-((4-chlorophenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-((4-chlorophenyl)(methyl)amino)-2-methy-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-(2,6-dimethyl-4-(2,2,2-trifluroethoxy)phenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((6-(2-methyl-6-(2-(2,2,2-trifluroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino) isonicotinicacid; (S)-3-(((6-(2-methyl-6-(2-(2,2,2-trifluroethoxy)phenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl) methyl)amino) isonicotinicacid;(R)-3-(((6-(2-cyclopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-(2-cyclopropylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid; (R)-3-(((6-(4-dimethylamino)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-(4-dimethylamino)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-methyl-6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-6-(methyl(4-(tetrahydro-2H-pyran-4-yl)phenyl)amino)-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-methyl-6-(methyl(4-(3,3,3-trifluoro-propyl)phenyl)amino)-1,2,3,4-tetrahydroisoquino-lin-1-yl)methyl)amino)isonicotinic acid;(S)-3-(((2-methyl-6-(methyl(4-(3,33-trifluoro-propyl)phenyl)amino)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino)isonicotinic acid; (R)-3-(((6-(4-(2-cyclopropylethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-(4-(2-cyclopropylethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl) amino)isonicotinic acid;(R)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-((4-cyclobutylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1l-yl)methyl)amino) isonicotinic acid;(S)-3-(((6-((4-cyclopentylphenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid; (R)-3-(((6-((4-cyclobutylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid; (S)-3-(((6-((4-cyclobutylmethyl)phenyl)(methyl)amino)-2-methyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)methyl)amino)isonicotinic acid;(R)-3-(((2-methyl-6-(6-methyl-2,3-dihydrobenzo-furan-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-6-(6-methyl-2,3-dihydrobenzo-furan-5-yl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((2-methyl-6-(5-methyl-2,3-dihydro-benzofuran-4-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino) isonicotinic acid;(S)-3-(((2-methyl-6-(5-methyl-2,3-dihydro-benzofuran-4-yl)-1,2,3,4-tetrahydroiso-quinolin-1-yl)methyl)amino) isonicotinic acid;(R)-3-(((2-methyl-6-(phenylthio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid; and(S)-3-(((2-methyl-6-(phenylthio)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)amino)isonicotinic acid.
 4. A pharmaceutical composition comprising thecompound of claim 3 and at least one pharmaceutically acceptableexcipient.